Treg cells in autoimmunity: from identification to Treg-based therapies

1.

MCintire KR, Sell S, Miller JF (1964) Pathogenesis of the post-neonatal thymectomy wasting syndrome. Nature 204:151–155CrossRefPubMed

2.

Nishizuka Y, Sakakura T (1969) Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science. 166:753–755CrossRefPubMed

3.

Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMed

4.

Malek TR, Yu A, Vincek V, Scibelli P, Kong L (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178CrossRefPubMed

5.

Furtado GC, Curotto de Lafaille MA, Kutchukhidze N, Lafaille JJ (2002) Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J Exp Med 196:851–857CrossRefPubMedPubMedCentral

6.

Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS et al (2012) A multiply redundant genetic switch “locks in” the transcriptional signature of regulatory T cells. Nat Immunol 13:972–980. https://doi.org/10.1038/ni.2420 CrossRefPubMedPubMedCentral

7.

Rudra D, deRoos P, Chaudhry A, Niec RE, Arvey A, Samstein RM et al (2012) Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 13:1010–1019. https://doi.org/10.1038/ni.2402 CrossRefPubMedPubMedCentral

8.

Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4:330–336. https://doi.org/10.1038/ni904 CrossRefPubMed

9.

Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21. https://doi.org/10.1038/83713 CrossRefPubMed

10.

Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73. https://doi.org/10.1038/83784 CrossRefPubMed

11.

Wildin RS, Smyk-Pearson S, Filipovich AH (2002) Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39:537–545CrossRefPubMedPubMedCentral

12.

Kim JM, Rasmussen JP, Rudensky AY (2007) Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 8:191–197. https://doi.org/10.1038/ni1428 CrossRefPubMed

13.

Hori S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061. https://doi.org/10.1126/science.1079490 CrossRefPubMed

14.

Ohkura N, Kitagawa Y, Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38:414–423. https://doi.org/10.1016/j.immuni.2013.03.002 CrossRefPubMed

15.

Thurman RE, Rynes E, Humbert R, Vierstra J, Maurano MT, Haugen E et al (2012) The accessible chromatin landscape of the human genome. Nature 489:75–82. https://doi.org/10.1038/nature11232 CrossRefPubMedPubMedCentral

16.

Schubert LA, Jeffery E, Zhang Y, Ramsdell F, Ziegler SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 276:37672–37679CrossRefPubMed

17.

Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY (2012) Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150:29–38. https://doi.org/10.1016/j.cell.2012.05.031 CrossRefPubMedPubMedCentral

18.

van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YYJ, Beekman JM, van Beekum O et al (2010) Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115:965–974. https://doi.org/10.1182/blood-2009-02-207118 CrossRefPubMed

19.

Deng G, Nagai Y, Xiao Y, Li Z, Dai S, Ohtani T et al (2015) Pim-2 kinase influences regulatory T cell function and stability by mediating Foxp3 protein N-terminal phosphorylation. J Biol Chem 290:20211–20220. https://doi.org/10.1074/jbc.M115.638221 CrossRefPubMedPubMedCentral

20.

Li Z, Lin F, Zhuo C, Deng G, Chen Z, Yin S et al (2014) PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J Biol Chem 289:26872–26881. https://doi.org/10.1074/jbc.M114.586651 CrossRefPubMedPubMedCentral

21.

Morawski PA, Mehra P, Chen C, Bhatti T, Wells AD (2013) Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J Biol Chem 288:24494–24502. https://doi.org/10.1074/jbc.M113.467704 CrossRefPubMedPubMedCentral

22.

Morikawa H, Ohkura N, Vandenbon A, Itoh M, Nagao-Sato S, Kawaji H et al (2014) Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc Natl Acad Sci 111:5289–5294. https://doi.org/10.1073/pnas.1312717110 CrossRefPubMedPubMedCentral

23.

Arvey A, van der Veeken J, Samstein RM, Feng Y, Stamatoyannopoulos JA, Rudensky AY (2014) Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Publ Group 15:580–587. https://doi.org/10.1038/ni.2868 CrossRef

24.

Beyer M, Thabet Y, Müller R-U, Sadlon T, Classen S, Lahl K et al (2011) Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol 12:898–907. https://doi.org/10.1038/ni.2084 CrossRefPubMedPubMedCentral

25.

Marson A, Kretschmer K, Frampton GM, Jacobsen ES, Polansky JK, MacIsaac KD et al (2007) Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445:931–935. https://doi.org/10.1038/nature05478 CrossRefPubMedPubMedCentral

26.

Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA et al (2007) Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445:771–775. https://doi.org/10.1038/nature05543 CrossRefPubMed

27.

Darce J, Rudra D, Li L, Nishio J, Cipolletta D et al (2012) An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes. Immunity 36:731–741. https://doi.org/10.1016/j.immuni.2012.04.007 CrossRefPubMedPubMedCentral

28.

Bettelli E, Dastrange M, Oukka M (2005) Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci 102:5138–5143. https://doi.org/10.1073/pnas.0501675102 CrossRefPubMedPubMedCentral

29.

Xiao Y, Nagai Y, Deng G, Ohtani T, Zhu Z, Zhou Z et al (2014) Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep 7:1471–1480. https://doi.org/10.1016/j.celrep.2014.04.021 CrossRefPubMedPubMedCentral

30.

Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF et al (2009) Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325:1142–1146. https://doi.org/10.1126/science.1176077 CrossRefPubMedPubMedCentral

31.

Tone Y, Furuuchi K, Kojima Y, Tykocinski ML, Greene MI, Tone M (2008) Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 9:194–202. https://doi.org/10.1038/ni1549 CrossRefPubMed

32.

Bruno L, Mazzarella L, Hoogenkamp M, Hertweck A, Cobb BS, Sauer S et al (2009) Runx proteins regulate Foxp3 expression. J Exp Med 206:2329–2337. https://doi.org/10.1084/jem.20090226 CrossRefPubMedPubMedCentral

33.

Vanvalkenburgh J, Albu DI, Bapanpally C, Casanova S, Califano D, Jones DM et al (2011) Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease. J Exp Med 208:2069–2081. https://doi.org/10.1084/jem.20102683 CrossRefPubMedPubMedCentral

34.

Samstein RM, Arvey A, Josefowicz SZ, Peng X, Reynolds A, Sandstrom R et al (2012) Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151:153–166. https://doi.org/10.1016/j.cell.2012.06.053 CrossRefPubMedPubMedCentral

35.

Kwon H-K, Chen H-M, Mathis D, Benoist C (2017) Different molecular complexes that mediate transcriptional induction and repression by FoxP3. Nat Immunol 18:1238–1248. https://doi.org/10.1038/ni.3835 CrossRefPubMedPubMedCentral

36.

Dominguez-Villar M, Hafler DA (2018) Regulatory T cells in autoimmune disease. Nat Immunol 1–9. https://doi.org/10.1038/s41590-018-0120-4.

37.

Polansky JK, Schreiber L, Thelemann C, Ludwig L, Krüger M, Baumgrass R et al (2010) Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med 88:1029–1040. https://doi.org/10.1007/s00109-010-0642-1 CrossRefPubMed

38.

Kim H-P, Leonard WJ (2007) CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204:1543–1551. https://doi.org/10.1084/jem.20070109 CrossRefPubMedPubMedCentral

39.

Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–812. https://doi.org/10.1038/nature08750 CrossRefPubMedPubMedCentral

40.

Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky AY (2014) Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158:749–763. https://doi.org/10.1016/j.cell.2014.07.031 CrossRefPubMedPubMedCentral

41.

Li X, Liang Y, LeBlanc M, Benner C, Zheng Y (2014) Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158:734–748. https://doi.org/10.1016/j.cell.2014.07.030 CrossRefPubMedPubMedCentral

42.

Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J et al (2007) DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol 37:2378–2389. https://doi.org/10.1002/eji.200737594 CrossRefPubMed

43.

Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J et al (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5:e38. https://doi.org/10.1371/journal.pbio.0050038 CrossRefPubMedPubMedCentral

44.

Wei G, Wei L, Zhu J, Zang C, Hu-Li J, Yao Z et al (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155–167. https://doi.org/10.1016/j.immuni.2008.12.009 CrossRefPubMedPubMedCentral

45.

Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395. https://doi.org/10.1038/cr.2011.22 CrossRefPubMedPubMedCentral

46.

Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drablos F et al (2015) Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells. Science 347:1010–1014. https://doi.org/10.1126/science.1259418 CrossRefPubMedPubMedCentral

47.

Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH et al (2013) Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153:307–319. https://doi.org/10.1016/j.cell.2013.03.035 CrossRefPubMedPubMedCentral

48.

Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA et al (2013) Super-enhancers in the control of cell identity and disease. Cell. 155:934–947. https://doi.org/10.1016/j.cell.2013.09.053 CrossRefPubMed

49.

Vahedi G, Kanno Y, Furumoto Y, Jiang K, Parker SCJ, Erdos MR et al (2015) Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520:558–562. https://doi.org/10.1038/nature14154 CrossRefPubMedPubMedCentral

50.

Kitagawa Y, Ohkura N, Kidani Y, Vandenbon A, Hirota K, Kawakami R et al (2016) Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat Immunol 18:173–183. https://doi.org/10.1038/ni.2590 CrossRefPubMedPubMedCentral

51.

Josefowicz SZ, Lu L-F, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564. https://doi.org/10.1146/annurev.immunol.25.022106.141623 CrossRefPubMedPubMedCentral

52.

Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S et al (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14:307–308. https://doi.org/10.1038/ni.2554 CrossRefPubMed

53.

Burzyn D, Benoist C, Mathis D (2013) Regulatory T cells in nonlymphoid tissues. Nat Immunol 14:1007–1013. https://doi.org/10.1038/ni.2683 CrossRefPubMedPubMedCentral

54.

Yamaguchi T, Wing JB, Sakaguchi S (2011) Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol 23:424–430. https://doi.org/10.1016/j.smim.2011.10.002 CrossRefPubMed

55.

Shevach EM (2018) Foxp3+ T regulatory cells: still many unanswered questions—a perspective after 20 years of study. Front Immun 9:389. https://doi.org/10.1056/NEJMoa1105143 CrossRef

56.

Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z et al (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322:271–275. https://doi.org/10.1126/science.1160062 CrossRefPubMed

57.

Wing JB, Ise W, Kurosaki T, Sakaguchi S (2014) Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity 41:1013–1025. https://doi.org/10.1016/j.immuni.2014.12.006 CrossRefPubMed

58.

Sage PT, Paterson AM, Lovitch SB, Sharpe AH (2014) The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41:1026–1039. https://doi.org/10.1016/j.immuni.2014.12.005 CrossRefPubMedPubMedCentral

59.

Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT et al (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345:1623–1627. https://doi.org/10.1126/science.1255904 CrossRefPubMedPubMedCentral

60.

Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A et al (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med 20:1410–1416. https://doi.org/10.1038/nm.3746 CrossRefPubMedPubMedCentral

61.

Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F (2006) Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology 118:240–249. https://doi.org/10.1111/j.1365-2567.2006.02362.x CrossRefPubMedPubMedCentral

62.

Schmidt A, Oberle N, Krammer PH (2012) Molecular mechanisms of Treg-mediated T cell suppression. Front Immun 3:51. https://doi.org/10.3389/fimmu.2012.00051 CrossRef

63.

Gondek DC, Devries V, Nowak EC, Lu L-F, Bennett KA, Scott ZA et al (2008) Transplantation survival is maintained by granzyme B+ regulatory cells and adaptive regulatory T cells. J Immunol 181:4752–4760CrossRefPubMed

64.

Yamaguchi T, Kishi A, Osaki M, Morikawa H, Prieto-Martin P, Wing K et al (2013) Construction of self-recognizing regulatory T cells from conventional T cells by controlling CTLA-4 and IL-2 expression. Proc Natl Acad Sci 110:E2116–E2125. https://doi.org/10.1073/pnas.1307185110 CrossRefPubMedPubMedCentral

65.

Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8:277–284. https://doi.org/10.1038/ni1437 CrossRefPubMed

66.

Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S (2009) Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci 106:1903–1908. https://doi.org/10.1073/pnas.0811556106 CrossRefPubMedPubMedCentral

67.

Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D et al (2010) Stability of the regulatory T cell lineage in vivo. Science 329:1667–1671. https://doi.org/10.1126/science.1191996 CrossRefPubMedPubMedCentral

68.

Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martínez-Llordella M, Ashby M et al (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10:1000–1007. https://doi.org/10.1038/ni.1774 CrossRefPubMedPubMedCentral

69.

Hoffmann P, Boeld TJ, Eder R, Huehn J, Floess S, Wieczorek G et al (2018) Regulatory T cells in the treatment of disease. Nat Publ Group 17:823–844. https://doi.org/10.1038/nrd.2018.148 CrossRef

70.

Koenen HJPM, Smeets RL, Vink PM, van Rijssen E, Boots AMH, Joosten I (2008) Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112:2340–2352. https://doi.org/10.1182/blood-2008-01-133967 CrossRefPubMed

71.

Laurence A, Amarnath S, Mariotti J, Kim YC, Foley J, Eckhaus M et al (2012) STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37:209–222. https://doi.org/10.1016/j.immuni.2012.05.027 CrossRefPubMedPubMedCentral

72.

Duarte JH, Zelenay S, Bergman M-L, Martins AC, Demengeot J (2009) Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 39:948–955. https://doi.org/10.1002/eji.200839196 CrossRefPubMed

73.

Oldenhove G, Bouladoux N, Wohlfert EA, Hall JA, Chou D, Dos Santos L et al (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31:772–786. https://doi.org/10.1016/j.immuni.2009.10.001 CrossRefPubMedPubMedCentral

74.

Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H et al (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949–962. https://doi.org/10.1016/j.immuni.2013.10.016 CrossRefPubMedPubMedCentral

75.

Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T et al (2013) Pathogenic conversion of Foxp3. Nat Med 20:62–68. https://doi.org/10.1038/nm.3432 CrossRefPubMed

76.

Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10:595–602. https://doi.org/10.1038/ni.1731 CrossRefPubMedPubMedCentral

77.

Koch MA, Thomas KR, Perdue NR, Smigiel KS, Srivastava S, Campbell DJ (2012) T-bet+ Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2. Immunity 37:501–510. https://doi.org/10.1016/j.immuni.2012.05.031 CrossRefPubMedPubMedCentral

78.

Levine AG, Medoza A, Hemmers S, Moltedo B, Niec RE, Schizas M et al (2017) Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546:421–425. https://doi.org/10.1038/528S132a CrossRefPubMedPubMedCentral

79.

McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA et al (2011) Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 186:3918–3926. https://doi.org/10.4049/jimmunol.1003099 CrossRefPubMed

80.

Kitz A, de Marcken M, Gautron A-S, Mitrovic M, Hafler DA, Dominguez-Villar M (2016) AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep 17:1169–1183. https://doi.org/10.15252/embr.201541905 CrossRefPubMedPubMedCentral

81.

Arterbery AS, Osafo-Addo A, Avitzur Y, Ciarleglio M, Deng Y, Lobritto SJ et al (2016) Production of proinflammatory cytokines by monocytes in liver-transplanted recipients with de novo autoimmune hepatitis is enhanced and induces TH1-like regulatory T cells. J Immunol 196:4040–4051. https://doi.org/10.4049/jimmunol.1502276 CrossRefPubMed

82.

Chaudhry A, Rudra D, Treuting P, Samstein RM, Liang Y, Kas A et al (2009) CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326:986–991. https://doi.org/10.1126/science.1172702 CrossRefPubMedPubMedCentral

83.

Beriou G, Costantino CM, Ashley CW, Yang L, Kuchroo VK, Baecher-Allan C et al (2009) IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113:4240–4249. https://doi.org/10.1182/blood-2008-10-183251 CrossRefPubMedPubMedCentral

84.

Ayyoub M, Deknuydt F, Raimbaud I, Dousset C, Leveque L, Bioley G et al (2009) Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineage-specific transcription factor RORgamma t. Proc Natl Acad Sci 106:8635–8640. https://doi.org/10.1073/pnas.0900621106 CrossRefPubMedPubMedCentral

85.

Singh K, Gatzka M, Peters T, Borkner L, Hainzl A, Wang H et al (2013) Reduced CD18 levels drive regulatory T cell conversion into Th17 cells in the CD18hypo PL/J mouse model of psoriasis. J Immunol 190:2544–2553. https://doi.org/10.4049/jimmunol.1202399 CrossRefPubMed

86.

Sefik E, Geva-Zatorsky N, Oh S, Konnikova L, Zemmour D, McGuire AM et al (2015) Individual intestinal symbionts induce a distinct population of RORγ<sup>+</sup> regulatory T cells. Science 349:993CrossRefPubMedPubMedCentral

87.

Yang B-H, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M et al (2016) Foxp3(+) T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9:444–457. https://doi.org/10.1038/mi.2015.74 CrossRefPubMed

88.

Kluger MA, Luig M, Wegscheid C, Goerke B, Paust H-J, Brix SR et al (2014) Stat3 programs Th17-specific regulatory T cells to control GN. J Am Soc Nephrol 25:1291–1302. https://doi.org/10.1681/ASN.2013080904 CrossRefPubMedPubMedCentral

89.

Kluger MA, Melderis S, Nosko A, Goerke B, Luig M, Meyer MC et al (2016) Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus. Kidney Int 89:158–166. https://doi.org/10.1038/ki.2015.296 CrossRefPubMed

90.

Zheng Y, Chaudhry A, Kas A, de Roos P, Kim JM, Chu T-T et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458:351–356. https://doi.org/10.1038/nature07674 CrossRefPubMedPubMedCentral

91.

Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH et al (2011) GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J Clin Invest 121:4503–4515. https://doi.org/10.1172/JCI57456DS1 CrossRefPubMedPubMedCentral

92.

Rivas MN, Burton OT, Wise P, Charbonnier L-M, Georgiev P, Oettgen HC et al (2015) Regulatory T cell reprogramming toward a Th2-cell- like lineage impairs oral tolerance and promotes food allergy. Immunity 42:512–523. https://doi.org/10.1016/j.immuni.2015.02.004 CrossRefPubMedCentral

93.

KG MD, Dawson NA, Huang Q, Dunne JV, Levings MK, Broady R (2015) Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J Allergy Clin Immunol 135:946–955.e9. https://doi.org/10.1016/j.jaci.2014.12.1932 CrossRef

94.

Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S et al (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701–1711. https://doi.org/10.1084/jem.20060772 CrossRefPubMedPubMedCentral

95.

Klein S, Kretz CC, Krammer PH, Kuhn A (2010) CD127(low/−) and FoxP3(+) expression levels characterize different regulatory T-cell populations in human peripheral blood. J Investig Dermatol 130:492–499. https://doi.org/10.1038/jid.2009.313 CrossRefPubMed

96.

Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142CrossRefPubMed

97.

Piconese S, Valzasina B, Colombo MP (2008) OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection. J Exp Med 205:825–839. https://doi.org/10.1084/jem.20071341 CrossRefPubMedPubMedCentral

98.

Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A et al (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30:899–911. https://doi.org/10.1016/j.immuni.2009.03.019 CrossRefPubMed

99.

Malek TR (2008) The biology of interleukin-2. Annu Rev Immunol 26:453–479. https://doi.org/10.1146/annurev.immunol.26.021607.090357 CrossRefPubMed

100.

Bernasconi A, Marino R, Ribas A, Rossi J, Ciaccio M, Oleastro M et al (2006) Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118:e1584–e1592. https://doi.org/10.1542/peds.2005-2882 CrossRefPubMed

101.

Nadeau K, Hwa V, Rosenfeld RG (2011) STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr 158:701–708. https://doi.org/10.1016/j.jpeds.2010.12.042 CrossRefPubMed

102.

Charbonnier L-M, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT et al (2015) Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol 135:217–227. https://doi.org/10.1016/j.jaci.2014.10.019 CrossRefPubMed

103.

Bonelli M, Savitskaya A, Steiner CW, Rath E, Smolen JS, Scheinecker C (2009) Phenotypic and functional analysis of CD4+CD25-Foxp3+ T cells in patients with systemic lupus erythematosus. J Immunol 182:1689–1695. https://doi.org/10.4049/jimmunol.182.3.1689 CrossRefPubMed

104.

Bonelli M, Schl LG, Blüml S, Karonitsch T, Steiner C-W, Steiner GN et al (2014) T cells: a marker for lupus nephritis? 16:1–11. https://doi.org/10.1186/ar4553

105.

Ferreira RC, Simons HZ, Thompson WS, Rainbow DB, Yang X, Cutler AJ et al (2017) Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity. J Autoimmun 84:75–86. https://doi.org/10.1016/j.jaut.2017.07.009 CrossRefPubMedPubMedCentral

106.

Mesquita D, Kirsztajn GM, Franco MF, Reis LA, Perazzio SF, Mesquita FV et al (2018) CD4+ T helper cells and regulatory T cells in active lupus nephritis: an imbalance towards a predominant Th1 response? Clin Exp Immunol 191:50–59. https://doi.org/10.1111/cei.13050 CrossRefPubMed

107.

Singla S, Wenderfer SE, Muscal E, Sagcal-Gironella ACP, Orange JS, Makedonas G (2017) Changes in frequency and activation status of major CD4(+) T-cell subsets after initiation of immunosuppressive therapy in a patient with new diagnosis childhood-onset systemic lupus erythematosus. Front Pediatr 5:104. https://doi.org/10.3389/fped.2017.00104 CrossRefPubMedPubMedCentral

108.

Eltayeb AA, Sayed DM, Afifi NA, Ibrahim MA, Sheref TM (2014) Regulatory T cell subsets in children with systemic lupus erythematosus. Clin Rheumatol 33:1085–1091. https://doi.org/10.1007/s10067-014-2636-9 CrossRefPubMed

109.

Prado C, de Paz B, López P, Gomez J, Rodríguez-Carrio J, Suárez A (2013) Relationship between FOXP3 positive populations and cytokine production in systemic lupus erythematosus. Cytokine 61:90–96. https://doi.org/10.1016/j.cyto.2012.08.033 CrossRefPubMed

110.

Yan B, Ye S, Chen G, Kuang M, Shen N, Chen S (2008) Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-α–producing antigen-presenting cells. Arthritis Rheum 58:801–812. https://doi.org/10.1002/art.23268 CrossRefPubMed

111.

Azab NA, Bassyouni IH, Emad Y, Abd El-Wahab GA, Hamdy G, Mashahit MA (2008) CD4+CD25+ regulatory T cells (TREG) in systemic lupus erythematosus (SLE) patients: the possible influence of treatment with corticosteroids. Clin Immunol 127:151–157. https://doi.org/10.1016/j.clim.2007.12.010 CrossRefPubMed

112.

Suarez A, Lopez P, Gomez J, Gutierrez C (2006) Enrichment of CD4+ CD25high T cell population in patients with systemic lupus erythematosus treated with glucocorticoids. Ann Rheum Dis 65:1512–1517. https://doi.org/10.1136/ard.2005.049924 CrossRefPubMedPubMedCentral

113.

Rodriguez-Reyna TS, Furuzawa-Carballeda J, Cabiedes J, Fajardo-Hermosillo LD, Martinez-Reyes C, Diaz-Zamudio M et al (2012) Th17 peripheral cells are increased in diffuse cutaneous systemic sclerosis compared with limited illness: a cross-sectional study. Rheumatol Int 32:2653–2660. https://doi.org/10.1007/s00296-011-2056-y CrossRefPubMed

114.

Pan X, Yuan X, Zheng Y, Wang W, Shan J, Lin F et al (2012) Increased CD45RA+ FoxP3(low) regulatory T cells with impaired suppressive function in patients with systemic lupus erythematosus. PLoS One 7:e34662CrossRefPubMedPubMedCentral

115.

Mesquita D, de Melo Cruvinel W, Araujo J, Pucci F, Salmazi K, Kallas E et al (2011) Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells. Scand J Rheumatol 40:41–50. https://doi.org/10.3109/03009742.2010.489229 CrossRefPubMed

116.

Banica L, Besliu A, Pistol G, Stavaru C, Ionescu R, Forsea A-M et al (2009) Quantification and molecular characterization of regulatory T cells in connective tissue diseases. Autoimmunity 42:41–49. https://doi.org/10.1080/08916930802282651 CrossRefPubMed

117.

Atfy M, Amr GE, Elnaggar AM, Labib HA, Esh A, Elokely AM (2009) Impact of CD4+CD25high regulatory T-cells and FoxP3 expression in the peripheral blood of patients with systemic lupus erythematosus. Egypt J Immunol 16:117–126PubMed

118.

Lee H-Y, Hong Y-K, Yun H-J, Kim Y-M, Kim J-R, Yoo W-H (2008) Altered frequency and migration capacity of CD4+CD25+ regulatory T cells in systemic lupus erythematosus. Rheumatology (Oxford) 47:789–794. https://doi.org/10.1093/rheumatology/ken108 CrossRef

119.

Hu S, Xiao W, Kong F, Ke D, Qin R, Su M (2008) Regulatory T cells and their molecular markers in peripheral blood of the patients with systemic lupus erythematosus. J Huazhong Univ Sci Technolog Med Sci 28:549–552. https://doi.org/10.1007/s11596-008-0513-y CrossRefPubMed

120.

Zhao S-S, Li X-M, Li X-P, Zhai Z-M, Chen Z, Ma Y et al (2008) Expression of CD4+ CD25+ CD127(low/−) T cells in patients with systemic lupus erythematosus. Zhonghua Yi Xue Za Zhi 88:453–456PubMed

121.

Hahn BH, Anderson M, Le E, La Cava A (2008) Anti-DNA Ig peptides promote Treg cell activity in systemic lupus erythematosus patients. Arthritis Rheum 58:2488–2497. https://doi.org/10.1002/art.23609 CrossRefPubMed

122.

Barath S, Aleksza M, Tarr T, Sipka S, Szegedi G, Kiss E (2007) Measurement of natural (CD4+CD25high) and inducible (CD4+IL-10+) regulatory T cells in patients with systemic lupus erythematosus. Lupus 16:489–496. https://doi.org/10.1177/0961203307080226 CrossRefPubMed

123.

Lyssuk EY, Torgashina AV, Soloviev SK, Nassonov EL, Bykovskaia SN (2007) Reduced number and function of CD4+CD25highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus. Adv Exp Med Biol 601:113–119CrossRefPubMed

124.

Crispín JC, Martinez A, Alcocer-Varela J (2003) Quantification of regulatory T cells in patients with systemic lupus erythematosus. J Autoimmun 21:273–276CrossRefPubMed

125.

Wang X, Qiao Y, Yang L, Song S, Han Y, Tian Y et al (2017) Leptin levels in patients with systemic lupus erythematosus inversely correlate with regulatory T cell frequency. Lupus 26:1401–1406. https://doi.org/10.1177/0961203317703497 CrossRefPubMed

126.

Margiotta D, Navarini L, Vadacca M, Basta F, Lo Vullo M, Pignataro F et al (2016) Relationship between leptin and regulatory T cells in systemic lupus erythematosus: preliminary results. Eur Rev Med Pharmacol Sci 20:636–641PubMed

127.

Zabinska M, Krajewska M, Koscielska-Kasprzak K, Jakuszko K, Bartoszek D, Myszka M et al (2016) CD4(+)CD25(+)CD127(−) and CD4(+)CD25(+)Foxp3(+) regulatory T cell subsets in mediating autoimmune reactivity in systemic lupus erythematosus patients. Arch Immunol Ther Exp 64:399–407. https://doi.org/10.1007/s00005-016-0399-5 CrossRef

128.

Legorreta-Haquet MV, Chavez-Rueda K, Chavez-Sanchez L, Cervera-Castillo H, Zenteno-Galindo E, Barile-Fabris L et al (2016) Function of Treg cells decreased in patients with systemic lupus erythematosus due to the effect of prolactin. Medicine (Baltimore) 95:e2384CrossRef

129.

Dal Ben ERR, do Prado CH, Baptista TSA, Bauer ME, Staub HL (2014) Patients with systemic lupus erythematosus and secondary antiphospholipid syndrome have decreased numbers of circulating CD4(+)CD25(+)Foxp3(+) Treg and CD3(−)CD19(+) B cells. Rev Bras Reumatol 54:241–246CrossRefPubMed

130.

Tselios K, Sarantopoulos A, Gkougkourelas I, Boura P (2014) CD4+CD25highFOXP3+ T regulatory cells as a biomarker of disease activity in systemic lupus erythematosus: a prospective study. Clin Exp Rheumatol 32:630–639PubMed

131.

Szmyrka-Kaczmarek M, Kosmaczewska A, Ciszak L, Szteblich A, Wiland P (2014) Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus. Postepy Hig Med Dosw (Online) 68:893–898CrossRef

132.

Longhi MS, Ma Y, Grant CR, Samyn M, Gordon P, Mieli-Vergani G et al (2013) T-regs in autoimmune hepatitis-systemic lupus erythematosus/mixed connective tissue disease overlap syndrome are functionally defective and display a Th1 cytokine profile. J Autoimmun 41:146–151. https://doi.org/10.1016/j.jaut.2012.12.003 CrossRefPubMed

133.

Kim J-R, Chae J-N, Kim S-H, Ha J-S (2012) Subpopulations of regulatory T cells in rheumatoid arthritis, systemic lupus erythematosus, and Behcet's disease. J Korean Med Sci 27:1009–1013. https://doi.org/10.3346/jkms.2012.27.9.1009 CrossRefPubMedPubMedCentral

134.

Xing Q, Su H, Cui J, Wang B (2012) Role of Treg cells and TGF-beta1 in patients with systemic lupus erythematosus: a possible relation with lupus nephritis. Immunol Investig 41:15–27. https://doi.org/10.3109/08820139.2011.578189 CrossRef

135.

Xing Q, Wang B, Su H, Cui J, Li J (2012) Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int 32:949–958. https://doi.org/10.1007/s00296-010-1771-0 CrossRefPubMed

136.

Henriques A, Ines L, Couto M, Pedreiro S, Santos C, Magalhaes M et al (2010) Frequency and functional activity of Th17, Tc17 and other T-cell subsets in systemic lupus erythematosus. Cell Immunol 264:97–103. https://doi.org/10.1016/j.cellimm.2010.05.004 CrossRefPubMed

137.

Suen J-L, Li H-T, Jong Y-J, Chiang B-L, Yen J-H (2009) Altered homeostasis of CD4 FoxP3 regulatory T-cell subpopulations in systemic lupus erythematosus. Immunology 127:196–205. https://doi.org/10.1111/j.1365-2567.2008.02937.x CrossRefPubMedPubMedCentral

138.

Lee J-H, Wang L-C, Lin Y-T, Yang Y-H, Lin D-T, Chiang B-L (2006) Inverse correlation between CD4+ regulatory T-cell population and autoantibody levels in paediatric patients with systemic lupus erythematosus. Immunology 117:280–286. https://doi.org/10.1111/j.1365-2567.2005.02306.x CrossRefPubMedPubMedCentral

139.

Miyara M, Amoura Z, Parizot C, Badoual C, Dorgham K, Trad S et al (2005) Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol 175:8392–8400CrossRefPubMed

140.

C. Jacquemin, J.-F. Augusto, M. Scherlinger, N. Gensous, E. Forcade, I. Douchet et al (2018) OX40L/OX40 axis impairs follicular and natural Treg function in human SLE. JCI Insight 3. https://doi.org/10.1172/jci.insight.122167.

141.

Vitales-Noyola M, Layseca-Espinosa E, Baranda L, Abud-Mendoza C, Nino-Moreno P, Monsiváis-Urenda A et al (2018) Analysis of sodium chloride intake and Treg/Th17 lymphocytes in healthy individuals and patients with rheumatoid arthritis or systemic lupus erythematosus. J Immunol Res 2018:9627806. https://doi.org/10.1155/2018/9627806 CrossRefPubMedPubMedCentral

142.

V. Kailashiya, U. Singh, R. Rana, N.K. Singh, D. Dash, J. Kailashiya (2018) Regulatory T cells and their association with serum markers and symptoms in systemic lupus erythematosus and rheumatoid arthritis, Immunol Investig 1–15. https://doi.org/10.1080/08820139.2018.1527852.

143.

Venigalla RKC, Tretter T, Krienke S, Max R, Eckstein V, Blank N et al (2008) Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high,CD127 −/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum 58:2120–2130. https://doi.org/10.1002/art.23556 CrossRefPubMed

144.

Kleczynska W, Jakiela B, Plutecka H, Milewski M, Sanak M, Musial J (2011) Imbalance between Th17 and regulatory T-cells in systemic lupus erythematosus. Folia Histochem Cytobiol 49:646–653CrossRefPubMed

145.

Liu X, Gao N, Li M, Xu D, Hou Y, Wang Q et al (2013) Elevated levels of CD4(+)CD25(+)FoxP3(+) T cells in systemic sclerosis patients contribute to the secretion of IL-17 and immunosuppression dysfunction. PLoS One 8:e64531CrossRefPubMedPubMedCentral

146.

Radstake TRDJ, van Bon L, Broen J, Wenink M, Santegoets K, Deng Y et al (2009) Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFbeta expression. PLoS One 4:e5981. https://doi.org/10.1371/journal.pone.0005981 CrossRefPubMedPubMedCentral

147.

Giovannetti A, Rosato E, Renzi C, Maselli A, Gambardella L, Giammarioli AM et al (2010) Analyses of T cell phenotype and function reveal an altered T cell homeostasis in systemic sclerosis. Correlations with disease severity and phenotypes. Clin Immunol 137:122–133. https://doi.org/10.1016/j.clim.2010.06.004 CrossRefPubMed

148.

Jiang N, Li M, Zeng X (2014) Correlation of Th17 cells and CD4(+)CD25(+) regulatory T cells with clinical parameters in patients with systemic sclerosis. Chin Med J 127:3557–3561PubMed

149.

Ugor E, Simon D, Almanzar G, Pap R, Najbauer J, Nemeth P et al (2017) Increased proportions of functionally impaired regulatory T cell subsets in systemic sclerosis. Clin Immunol 184:54–62. https://doi.org/10.1016/j.clim.2017.05.013 CrossRefPubMed

150.

Slobodin G, Ahmad MS, Rosner I, Peri R, Rozenbaum M, Kessel A et al (2010) Regulatory T cells (CD4(+)CD25(bright)FoxP3(+)) expansion in systemic sclerosis correlates with disease activity and severity. Cell Immunol 261:77–80. https://doi.org/10.1016/j.cellimm.2009.12.009 CrossRefPubMed

151.

Antiga E, Quaglino P, Bellandi S, Volpi W, Del Bianco E, Comessatti A et al (2010) Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea. Br J Dermatol 162:1056–1063. https://doi.org/10.1111/j.1365-2133.2010.09633.x CrossRefPubMed

152.

Papp G, Horvath IF, Barath S, Gyimesi E, Sipka S, Szodoray P et al (2011) Altered T-cell and regulatory cell repertoire in patients with diffuse cutaneous systemic sclerosis. Scand J Rheumatol 40:205–210. https://doi.org/10.3109/03009742.2010.528021 CrossRefPubMed

153.

Fenoglio D, Battaglia F, Parodi A, Stringara S, Negrini S, Panico N et al (2011) Alteration of Th17 and Treg cell subpopulations co-exist in patients affected with systemic sclerosis. Clin Immunol 139:249–257. https://doi.org/10.1016/j.clim.2011.01.013 CrossRefPubMed

154.

Mathian A, Parizot C, Dorgham K, Trad S, Arnaud L, Larsen M et al (2012) Activated and resting regulatory T cell exhaustion concurs with high levels of interleukin-22 expression in systemic sclerosis lesions. Ann Rheum Dis 71:1227–1234. https://doi.org/10.1136/annrheumdis-2011-200709 CrossRefPubMed

155.

Cordiali-Fei P, Mussi A, D'Agosto G, Trento E, Bordignon V, Trincone S et al (2013) Assessment of T regulatory cells and expanded profiling of autoantibodies may offer novel biomarkers for the clinical management of systemic sclerosis and undifferentiated connective tissue disease. Clin Dev Immunol 2013:390563. https://doi.org/10.1155/2013/390563 CrossRefPubMedPubMedCentral

156.

Wang YY, Wang Q, Sun XH, Liu RZ, Shu Y, Kanekura T et al (2014) DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br J Dermatol 171:39–47. https://doi.org/10.1111/bjd.12913 CrossRefPubMed

157.

Baraut J, Grigore EI, Jean-Louis F, Khelifa SH, Durand C, Verrecchia F et al (2014) Peripheral blood regulatory T cells in patients with diffuse systemic sclerosis (SSc) before and after autologous hematopoietic SCT: a pilot study. Bone Marrow Transplant 49:349–354. https://doi.org/10.1038/bmt.2013.202 CrossRefPubMed

158.

Kataoka H, Yasuda S, Fukaya S, Oku K, Horita T, Atsumi T et al (2015) Decreased expression of Runx1 and lowered proportion of Foxp3(+) CD25(+) CD4(+) regulatory T cells in systemic sclerosis. Mod Rheumatol 25:90–95. https://doi.org/10.3109/14397595.2014.899736 CrossRefPubMed

159.

Klein S, Kretz CC, Ruland V, Stumpf C, Haust M, Hartschuh W et al (2011) Reduction of regulatory T cells in skin lesions but not in peripheral blood of patients with systemic scleroderma. Ann Rheum Dis 70:1475–1481. https://doi.org/10.1136/ard.2009.116525 CrossRefPubMed

160.

Krasimirova E, Velikova T, Ivanova-Todorova E, Tumangelova-Yuzeir K, Kalinova D, Boyadzhieva V et al (2017) Treg/Th17 cell balance and phytohaemagglutinin activation of T lymphocytes in peripheral blood of systemic sclerosis patients. World J Exp Med 7:84–96. https://doi.org/10.5493/wjem.v7.i3.84 CrossRefPubMedPubMedCentral

161.

Han GM, O'Neil-Andersen NJ, Zurier RB, Lawrence DA (2008) CD4+CD25high T cell numbers are enriched in the peripheral blood of patients with rheumatoid arthritis. Cell Immunol 253:92–101. https://doi.org/10.1016/j.cellimm.2008.05.007 CrossRefPubMedPubMedCentral

162.

Dombrecht EJ, Aerts NE, Schuerwegh AJ, Hagendorens MM, Ebo DG, Van Offel JF et al (2006) Influence of anti-tumor necrosis factor therapy (adalimumab) on regulatory T cells and dendritic cells in rheumatoid arthritis. Clin Exp Rheumatol 24:31–37PubMed

163.

van Amelsfort JMR, Jacobs KMG, Bijlsma JWJ, Lafeber FPJG, Taams LS (2004) CD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 50:2775–2785. https://doi.org/10.1002/art.20499 CrossRefPubMed

164.

Dejaco C, Duftner C, Klauser A, Schirmer M (2010) Altered T-cell subtypes in spondyloarthritis, rheumatoid arthritis and polymyalgia rheumatica. Rheumatol Int 30:297–303. https://doi.org/10.1007/s00296-009-0949-9 CrossRefPubMed

165.

Cao D, van Vollenhoven R, Klareskog L, Trollmo C, Malmström V (2004) CD25brightCD4+ regulatory T cells are enriched in inflamed joints of patients with chronic rheumatic disease. Arthritis Res Ther 6:R335–R346CrossRefPubMedPubMedCentral

166.

Jiao Z, Wang W, Jia R, Li J, You H, Chen L et al (2007) Accumulation of FoxP3-expressing CD4+CD25+ T cells with distinct chemokine receptors in synovial fluid of patients with active rheumatoid arthritis. Scand J Rheumatol 36:428–433. https://doi.org/10.1080/03009740701482800 CrossRefPubMed

167.

Sempere-Ortells JM, Perez-Garcia V, Marin-Alberca G, Peris-Pertusa A, Benito JM, Marco FM et al (2009) Quantification and phenotype of regulatory T cells in rheumatoid arthritis according to disease activity score-28. Autoimmunity 42:636–645. https://doi.org/10.3109/08916930903061491 CrossRefPubMed

168.

Kawashiri S-Y, Kawakami A, Okada A, Koga T, Tamai M, Yamasaki S et al (2011) CD4+CD25(high)CD127(low/−) Treg cell frequency from peripheral blood correlates with disease activity in patients with rheumatoid arthritis. J Rheumatol 38:2517–2521. https://doi.org/10.3899/jrheum.110283 CrossRefPubMed

169.

Niu Q, Cai B, Huang Z-C, Shi Y-Y, Wang L-L (2012) Disturbed Th17/Treg balance in patients with rheumatoid arthritis. Rheumatol Int 32:2731–2736. https://doi.org/10.1007/s00296-011-1984-x CrossRefPubMed

170.

Samson M, Audia S, Janikashvili N, Ciudad M, Trad M, Fraszczak J et al (2012) Brief report: inhibition of interleukin-6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis. Arthritis Rheum 64:2499–2503. https://doi.org/10.1002/art.34477 CrossRefPubMed

171.

Lina C, Conghua W, Nan L, Ping Z (2011) Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis. J Clin Immunol 31:596–605. https://doi.org/10.1007/s10875-011-9542-6 CrossRefPubMed

172.

Zhang X, Zhang X, Zhuang L, Xu C, Li T, Zhang G et al (2018) Decreased regulatory T-cell frequency and interleukin-35 levels in patients with rheumatoid arthritis. Exp Ther Med 16:5366–5372PubMedPubMedCentral

173.

Wang L, Wang C, Jia X, Yu J (2018) Circulating exosomal miR-17 inhibits the induction of regulatory T cells via suppressing TGFBR II expression in rheumatoid arthritis. Cell Physiol Biochem 50:1754–1763. https://doi.org/10.1159/000494793 CrossRefPubMed

174.

Hashemi V, Farrokhi AS, Tanomand A, Babaloo Z, Hojjat-Farsangi M, Anvari E et al (2018) Polymorphism of Foxp3 gene affects the frequency of regulatory T cells and disease activity in patients with rheumatoid arthritis in Iranian population. Immunol Lett 204:16–22. https://doi.org/10.1016/j.imlet.2018.10.001 CrossRefPubMed

175.

Sun H, Gao W, Pan W, Zhang Q, Wang G, Feng D et al (2017) Tim3(+) Foxp3 (+) Treg cells are potent inhibitors of effector T cells and are suppressed in rheumatoid arthritis. Inflammation 40:1342–1350. https://doi.org/10.1007/s10753-017-0577-6 CrossRefPubMed

176.

Cao D, Malmström V, Baecher-Allan C, Hafler D, Klareskog L, Trollmo C (2003) Isolation and functional characterization of regulatory CD25brightCD4+ T cells from the target organ of patients with rheumatoid arthritis. Eur J Immunol 33:215–223. https://doi.org/10.1002/immu.200390024 CrossRefPubMed

177.

Mottonen M, Heikkinen J, Mustonen L, Isomaki P, Luukkainen R, Lassila O (2005) CD4+ CD25+ T cells with the phenotypic and functional characteristics of regulatory T cells are enriched in the synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol 140:360–367. https://doi.org/10.1111/j.1365-2249.2005.02754.x CrossRefPubMedPubMedCentral

178.

Liu M-F, Wang C-R, Fung L-L, Lin L-H, Tsai C-N (2005) The presence of cytokine-suppressive CD4+CD25+ T cells in the peripheral blood and synovial fluid of patients with rheumatoid arthritis. Scand J Immunol 62:312–317. https://doi.org/10.1111/j.1365-3083.2005.01656.x CrossRefPubMed

179.

Walter GJ, Evans HG, Menon B, Gullick NJ, Kirkham BW, Cope AP et al (2013) Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127(low) regulatory T cells. Arthritis Rheum 65:627–638. https://doi.org/10.1002/art.37832 CrossRefPubMedPubMedCentral

180.

Jandus C, Bioley G, Rivals J-P, Dudler J, Speiser D, Romero P (2008) Increased numbers of circulating polyfunctional Th17 memory cells in patients with seronegative spondylarthritides. Arthritis Rheum 58:2307–2317. https://doi.org/10.1002/art.23655 CrossRefPubMed

181.

Ji L, Geng Y, Zhou W, Zhang Z (2016) A study on relationship among apoptosis rates, number of peripheral T cell subtypes and disease activity in rheumatoid arthritis. Int J Rheum Dis 19:167–171. https://doi.org/10.1111/1756-185X.12211 CrossRefPubMed

182.

Wang M, Liu C, Bond A, Yang J, Zhou X, Wang J et al (2018) Dysfunction of regulatory T cells in patients with ankylosing spondylitis is associated with a loss of Tim-3. Int Immunopharmacol 59:53–60. https://doi.org/10.1016/j.intimp.2018.03.032 CrossRefPubMed

183.

Ciccia F, Accardo-Palumbo A, Giardina A, Di Maggio P, Principato A, Bombardieri M et al (2010) Expansion of intestinal CD4+CD25(high) Treg cells in patients with ankylosing spondylitis: a putative role for interleukin-10 in preventing intestinal Th17 response. Arthritis Rheum 62:3625–3634. https://doi.org/10.1002/art.27699 CrossRefPubMed

184.

Zhao S-S, Hu J-W, Wang J, Lou X-J, Zhou L-L (2011) Inverse correlation between CD4+ CD25high CD127low/− regulatory T-cells and serum immunoglobulin A in patients with new-onset ankylosing spondylitis. J Int Med Res 39:1968–1974. https://doi.org/10.1177/147323001103900543 CrossRefPubMed

185.

Guo H, Zheng M, Zhang K, Yang F, Zhang X, Han Q et al (2016) Functional defects in CD4(+) CD25(high) FoxP3(+) regulatory cells in ankylosing spondylitis. Sci Rep 6:37559. https://doi.org/10.1038/srep37559 CrossRefPubMedPubMedCentral

186.

Wang C, Liao Q, Hu Y, Zhong DA (2015) T lymphocyte subset imbalances in patients contribute to ankylosing spondylitis. Exp Ther Med 9:250–256CrossRefPubMed

187.

Ye L, Goodall JC, Zhang L, Putintseva EV, Lam B, Jiang L et al (2016) TCR usage, gene expression and function of two distinct FOXP3(+)Treg subsets within CD4(+)CD25(hi) T cells identified by expression of CD39 and CD45RO. Immunol Cell Biol 94:293–305. https://doi.org/10.1038/icb.2015.90 CrossRefPubMed

188.

Fattahi MJ, Ahmadi H, Jafarnezhad-Ansariha F, Mortazavi-Jahromi SS, Rehm BHA, Cuzzocrea S et al (2018) Oral administration effects of beta-d-mannuronic acid (M2000) on Th17 and regulatory T cells in patients with ankylosing spondylitis. Biomed Pharmacother 100:495–500. https://doi.org/10.1016/j.biopha.2018.02.059 CrossRefPubMed

189.

Yan B, Ye S, Chen G, Kuang M, Shen N, Chen S (2008) Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum 58:801–812. https://doi.org/10.1002/art.23268 CrossRefPubMed

190.

Valencia X, Yarboro C, Illei G, Lipsky PE (2007) Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol 178:2579–2588CrossRefPubMed

191.

Schaier M, Gottschalk C, Uhlmann L, Speer C, Kalble F, Eckstein V et al (2018) Immunosuppressive therapy influences the accelerated age-dependent T-helper cell differentiation in systemic lupus erythematosus remission patients. Arthritis Research & Therapy. 20:278. https://doi.org/10.1186/s13075-018-1778-6 CrossRef

192.

Rapetti L, Chavele K-M, Evans CM, Ehrenstein MR (2015) B cell resistance to Fas-mediated apoptosis contributes to their ineffective control by regulatory T cells in rheumatoid arthritis. Ann Rheum Dis 74:294–302. https://doi.org/10.1136/annrheumdis-2013-204049 CrossRefPubMed

193.

Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR (2008) Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci 105:19396–19401. https://doi.org/10.1073/pnas.0806855105 CrossRefPubMedPubMedCentral

194.

Nadkarni S, Mauri C, Ehrenstein MR (2007) Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 204:33–39. https://doi.org/10.1084/jem.20061531 CrossRefPubMedPubMedCentral

195.

Comte D, Karampetsou MP, Kis-Toth K, Yoshida N, Bradley SJ, Kyttaris VC et al (2016) CD4+ T cells from SLE patients respond poorly to exogenous IL-2. Arthritis Rheumatol. https://doi.org/10.1002/art.40014

196.

de Paz B, Prado C, Alperi-Lopez M, Ballina-Garcia FJ, Rodriguez-Carrio J, Lopez P et al (2012) Effects of glucocorticoid treatment on CD25-FOXP3+ population and cytokine-producing cells in rheumatoid arthritis. Rheumatology 51:1198–1207. https://doi.org/10.1093/rheumatology/kes039 CrossRefPubMed

197.

Fransson M, Burman J, Lindqvist C, Atterby C, Fagius J, Loskog A (2010) T regulatory cells lacking CD25 are increased in MS during relapse. Autoimmunity 43:590–597. https://doi.org/10.3109/08916930903541190 CrossRefPubMed

198.

Yang H-X, Zhang W, Zhao L-D, Li Y, Zhang F-C, Tang F-L et al (2009) Are CD4+CD25-Foxp3+ cells in untreated new-onset lupus patients regulatory T cells? Arthritis Res Ther 11:R153. https://doi.org/10.1186/ar2829 CrossRefPubMedPubMedCentral

199.

C. von Spee-Mayer, E. Siegert, D. Abdirama, A. Rose, A. Klaus, T. Alexander et al (2015) Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus, annals of the rheumatic diseases. Annrheumdis–2015–207776. https://doi.org/10.1136/annrheumdis-2015-207776.

200.

Moradi B, Schnatzer P, Hagmann S, Rosshirt N, Gotterbarm T, Kretzer JP et al (2014) CD4(+)CD25(+)/highCD127low/(−) regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints--analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res Ther 16:R97. https://doi.org/10.1186/ar4545 CrossRefPubMedPubMedCentral

201.

Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA et al (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 200:277–285CrossRefPubMedPubMedCentral

202.

Wu Y, Ren M, Yang R, Liang X, Ma Y, Tang Y et al (2011) Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4+CCR6+ Th/Treg cell subset imbalance in ankylosing spondylitis. Arthritis Res Ther 13:R29. https://doi.org/10.1186/ar3257 CrossRefPubMedPubMedCentral

203.

Dulic S, Vasarhelyi Z, Bajnok A, Szalay B, Toldi G, Kovacs L et al (2018) The impact of anti-TNF therapy on CD4+ and CD8+ cell subsets in ankylosing spondylitis. Pathobiology 85:201–210. https://doi.org/10.1159/000484250 CrossRefPubMed

204.

Liao H-T, Lin Y-F, Tsai C-Y, Chou C-T (2015) Regulatory T cells in ankylosing spondylitis and the response after adalimumab treatment. Joint Bone Spine 82:423–427. https://doi.org/10.1016/j.jbspin.2015.03.003 CrossRefPubMed

205.

Frantz C, Auffray C, Avouac J, Allanore Y (2018) Regulatory T cells in systemic sclerosis. Front Immun 9:490. https://doi.org/10.1182/blood-2015-06-649145 CrossRef

206.

Antiga E, Fabbri P, Caproni M (2010) Immunosuppressive therapy may affect the number of circulating regulatory cells in systemic sclerosis: pay attention to the patient selection criteria. Cell Immunol 264:186. https://doi.org/10.1016/j.cellimm.2010.06.007 CrossRefPubMed

207.

Huertas A, Phan C, Bordenave J, Tu L, Thuillet R, Le Hiress M et al (2016) Regulatory T cell dysfunction in idiopathic, heritable and connective tissue-associated pulmonary arterial hypertension. Chest 149:1482–1493. https://doi.org/10.1016/j.chest.2016.01.004 CrossRefPubMed

208.

Danikowski KM, Jayaraman S, Prabhakar BS (2017) Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation 14:117. https://doi.org/10.1186/s12974-017-0892-8 CrossRefPubMedPubMedCentral

209.

Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM et al (2005) Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52:2212–2221. https://doi.org/10.1002/art.21195 CrossRefPubMed

210.

Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T et al (2009) Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 58:652–662. https://doi.org/10.2337/db08-1168 CrossRefPubMedPubMedCentral

211.

Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK et al (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7:315ra189. https://doi.org/10.1126/scitranslmed.aad4134 CrossRefPubMedPubMedCentral

212.

Rossetti M, Spreafico R, Saidin S, Chua C, Moshref M, Leong JY et al (2015) Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region. J Immunol 194:113–124. https://doi.org/10.4049/jimmunol.1401145 CrossRefPubMed

213.

Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E et al (2011) Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 117:3921–3928. https://doi.org/10.1182/blood-2010-10-311894 CrossRefPubMed

214.

Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J et al (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117:1061–1070. https://doi.org/10.1182/blood-2010-07-293795 CrossRefPubMedPubMedCentral

215.

Martelli MF, Di Ianni M, Ruggeri L, Falzetti F, Carotti A, Terenzi A et al (2014) HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood 124:638–644. https://doi.org/10.1182/blood-2014-03-564401 CrossRefPubMed

216.

Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Derkowska I, Juscinska J et al (2014) Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin Immunol 153:23–30. https://doi.org/10.1016/j.clim.2014.03.016 CrossRefPubMed

217.

Kuhn C, Weiner HL (2016) Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy. 8:889–906. https://doi.org/10.2217/imt-2016-0049 CrossRefPubMed

218.

Spence A, Klementowicz JE, Bluestone JA, Tang Q (2015) Targeting Treg signaling for the treatment of autoimmune diseases. Curr Opin Immunol 37:11–20. https://doi.org/10.1016/j.coi.2015.09.002 CrossRefPubMedPubMedCentral

219.

Becker MO, Bruckner C, Scherer HU, Wassermann N, Humrich JY, Hanitsch LG et al (2011) The monoclonal anti-CD25 antibody basiliximab for the treatment of progressive systemic sclerosis: an open-label study. Ann Rheum Dis 70:1340–1341. https://doi.org/10.1136/ard.2010.137935 CrossRefPubMed

220.

Powell JD, Delgoffe GM (2010) The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33:301–311. https://doi.org/10.1016/j.immuni.2010.09.002 CrossRefPubMedPubMedCentral

221.

Battaglia M, Stabilini A, Roncarolo MG (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105:4743–4748. https://doi.org/10.1182/blood-2004-10-3932. CrossRefPubMed

222.

Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG (2006) Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177:8338–8347CrossRefPubMed

223.

Chatenoud L, Thervet E, Primo J, Bach JF (1994) Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci 91:123–127CrossRefPubMedPubMedCentral

224.

Herold KC, Hagopian W, Auger JA, Poumian-Ruiz E, Taylor L, Donaldson D et al (2002) Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med 346:1692–1698CrossRefPubMed

225.

Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G et al (2005) Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med 352:2598–2608. https://doi.org/10.1056/NEJMoa043980 CrossRefPubMed

226.

Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V et al (2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365:2067–2077. https://doi.org/10.1056/NEJMoa1105143 CrossRefPubMed

227.

Klatzmann D, Abbas AK (2015) The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat Rev Immunol 15:283–294. https://doi.org/10.1038/nri3823 CrossRefPubMed

228.

Yu A, Zhu L, Altman NH, Malek TR (2009) A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30:204–217. https://doi.org/10.1016/j.immuni.2008.11.014 CrossRefPubMedPubMedCentral

229.

Castro I, Yu A, Dee MJ, Malek TR (2011) The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development. J Immunol 187:5170–5182. https://doi.org/10.4049/jimmunol.1003961 CrossRefPubMed

230.

Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE et al (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36:847–856. https://doi.org/10.1016/j.immuni.2012.02.012 CrossRefPubMedPubMedCentral

231.

Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381. https://doi.org/10.1016/j.immuni.2007.02.009 CrossRefPubMed

232.

Spence A, Tang Q (2016) Restoring regulatory T cells in type 1 diabetes. Curr Diab Rep 16:110. https://doi.org/10.1007/s11892-016-0807-6 CrossRefPubMed

233.

Matsuoka K-I, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y et al (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 5:179ra43. https://doi.org/10.1126/scitranslmed.3005265 CrossRefPubMedPubMedCentral

234.

Castela E, Le Duff F, Butori C, Ticchioni M, Hofman P, Bahadoran P et al (2014) Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol 150:748–751. https://doi.org/10.1001/jamadermatol.2014.504 CrossRefPubMed

235.

He J, Zhang X, Wei Y, Sun X, Chen Y, Deng J et al (2016) Low-dose interleukin-2 treatment selectively modulates CD4. Nat Med 22:991–993. https://doi.org/10.1038/nm.4148 CrossRefPubMed

236.

Rosenzwajg M, Lorenzon R, Cacoub P, Pham HP, Pitoiset F, El Soufi K et al (2019) Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann Rheum Dis 78:209–217. https://doi.org/10.1136/annrheumdis-2018-214229 CrossRefPubMed

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Treg cells in autoimmunity: from identification to Treg-based therapies

Abstract

Leitlinien kompakt für die Innere Medizin

Neu im Fachgebiet Innere Medizin

Nach Herzinfarkt mit Typ-1-Diabetes schlechtere Karten als mit Typ 2?

15% bedauern gewählte Blasenkrebs-Therapie

Costims – das nächste heiße Ding in der Krebstherapie?

Perioperative Checkpointhemmer-Therapie verbessert NSCLC-Prognose

Update Innere Medizin

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2019

A new therapeutic target: the CD69-Myl9 system in immune responses

T cell pathology in skin inflammation

Pathogenicity of acquired immunity in human diseases

CD8+ T cell exhaustion

Regulation of T cell differentiation and function by epigenetic modification enzymes