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Medical Microbiology and Immunology

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09.03.2019 | Review

Fuel and brake of memory T cell inflation

verfasst von: Suzanne P. M. Welten, Nicolas S. Baumann, Annette Oxenius

Erschienen in: Medical Microbiology and Immunology | Ausgabe 3-4/2019

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Abstract

Memory T cell inflation is a process in which a large number of effector memory T cells accumulates in peripheral tissues. This phenomenon is observed upon certain low level persistent virus infections, but it is most commonly described upon infection with the β-herpesvirus Cytomegalovirus. Due to the induction of this large pool of functional effector CD8 T cells in peripheral tissues, the interest in using CMV-based vaccine vectors for vaccination purposes is rising. However, the exact mechanisms of memory T cell inflation are not yet fully understood. It is clear that repetitive exposure to antigen is a key determinant for memory inflation, and therefore the viral inoculum dose and the subsequent number of viral reactivation events strongly impact on the magnitude of the inflationary T cell pool. In addition, the number of CMV-specific CD8 T cells that is able to sense these reactivation events affects the size of the inflationary T cell pool. In the following, we will discuss factors that either promote or limit T cell inflation from both the virus and host perspective. These factors mostly operate by influencing the amount of available antigen or by affecting the T cell pool that is able to respond to the antigen. Furthermore, we will discuss the recent use of CMV-based vaccines in pre-clinical experimental settings, where these vectors have shown promising results by inducing prolonged effector memory T cell responses to foreign-introduced epitopes and thereby provided protection from subsequent virus or tumour challenges.

Martin MD, Badovinac VP (2018) Defining memory CD8 T cell. Front Immunol 9:2692PubMedPubMedCentral

Karrer U, Sierro S, Wagner M et al (2003) Memory inflation: continuous accumulation of antiviral CD8 + T cells over time. J Immunol 170(7):2022–2029 (*This article contains an errata: Karrer U, Sierro S, Wagner M et al (2003) Memory inflation: continuous accumulation of antiviral CD8 + T cells over time. J Immunol 171(7) 3895) PubMed

Klenerman P, Oxenius A (2016) T cell responses to cytomegalovirus. Nat Rev Immunol 16:367–377PubMed

O’hara GA, Welten SP, Klenerman P et al (2012) Memory T cell inflation: understanding cause and effect. Trends Immunol 33:84–90PubMed

Holtappels R, Pahl-Seibert MF, Thomas D et al (2000) Enrichment of immediate-early 1 (m123/pp89) peptide-specific CD8 T cells in a pulmonary CD62L(lo) memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J Virol 74:11495–11503PubMedPubMedCentral

Holtappels R, Thomas D, Podlech J et al (2002) Two antigenic peptides from genes m123 and m164 of murine cytomegalovirus quantitatively dominate CD8 T-cell memory in the H-2d haplotype. J Virol 76:151–164PubMedPubMedCentral

Panagioti E, Redeker A, Van Duikeren S et al (2016) The breadth of synthetic long peptide vaccine-induced CD8 + T cell responses determines the efficacy against mouse cytomegalovirus infection. PLoS Pathog 12:e1005895PubMedPubMedCentral

Karrer U, Wagner M, Sierro S et al (2004) Expansion of protective CD8 + T-cell responses driven by recombinant cytomegaloviruses. J Virol 78:2255–2264PubMedPubMedCentral

Dekhtiarenko I, Jarvis MA, Ruzsics Z et al (2013) The context of gene expression defines the immunodominance hierarchy of cytomegalovirus antigens. J Immunol 190:3399–3409PubMed

10.

Sierro S, Rothkopf R, Klenerman P (2005) Evolution of diverse antiviral CD8 + T cell populations after murine cytomegalovirus infection. Eur J Immunol 35:1113–1123PubMed

11.

Beyranvand Nejad E, Ratts RB, Panagioti E et al (2019) Demarcated thresholds of tumor-specific CD8 T cells elicited by MCMV-based vaccine vectors provide robust correlates of protection. J Immunother Cancer 7:25PubMedPubMedCentral

12.

Dekhtiarenko I, Ratts RB, Blatnik R et al (2016) Peptide processing is critical for T-cell memory inflation and may be optimized to improve immune protection by CMV-based vaccine vectors. PLoS Pathog 12:e1006072PubMedPubMedCentral

13.

Hutchinson S, Sims S, O’hara G et al (2011) A dominant role for the immunoproteasome in CD8 + T cell responses to murine cytomegalovirus. PLoS One 6:e14646PubMedPubMedCentral

14.

Munks MW, Cho KS, Pinto AK et al (2006) Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol 177:450–458PubMed

15.

Beswick M, Pachnio A, Al-Ali A et al (2013) An attenuated temperature-sensitive strain of cytomegalovirus (tsm5) establishes immunity without development of CD8(+) T cell memory inflation. J Med Virol 85:1968–1974PubMed

16.

Redeker A, Welten SP, Arens R (2014) Viral inoculum dose impacts memory T-cell inflation. Eur J Immunol 44:1046–1057PubMed

17.

Oduro JD, Redeker A, Lemmermann NA et al (2016) Murine cytomegalovirus (CMV) infection via the intranasal route offers a robust model of immunity upon mucosal CMV infection. J Gen Virol 97:185–195PubMed

18.

Snyder CM, Cho KS, Bonnett EL et al (2011) Sustained CD8 + T cell memory inflation after infection with a single-cycle cytomegalovirus. PLoS Pathog 7:e1002295PubMedPubMedCentral

19.

Torti N, Walton SM, Murphy KM et al (2011) Batf3 transcription factor-dependent DC subsets in murine CMV infection: differential impact on T-cell priming and memory inflation. Eur J Immunol 41:2612–2618PubMed

20.

Seckert CK, Schader SI, Ebert S et al (2011) Antigen-presenting cells of haematopoietic origin prime cytomegalovirus-specific CD8 T-cells but are not sufficient for driving memory inflation during viral latency. J Gen Virol 92:1994–2005PubMed

21.

Busche A, Jirmo AC, Welten SP et al (2013) Priming of CD8+ T cells against cytomegalovirus-encoded antigens is dominated by cross-presentation. J Immunol 190:2767–2777PubMed

22.

Snyder CM, Allan JE, Bonnett EL et al (2010) Cross-presentation of a spread-defective MCMV is sufficient to prime the majority of virus-specific CD8+ T cells. PLoS One 5:e9681PubMedPubMedCentral

23.

Welten SP, Redeker A, Franken KL et al (2013) CD27-CD70 costimulation controls T cell immunity during acute and persistent cytomegalovirus infection. J Virol 87:6851–6865PubMedPubMedCentral

24.

Arens R, Loewendorf A, Redeker A et al (2011) Differential B7-CD28 costimulatory requirements for stable and inflationary mouse cytomegalovirus-specific memory CD8 T cell populations. J Immunol 186:3874–3881PubMedPubMedCentral

25.

Welten SP, Redeker A, Franken KL et al (2015) The viral context instructs the redundancy of costimulatory pathways in driving CD8(+) T cell expansion. Elife 4:e07486PubMedCentral

26.

Welten SPM, Redeker A, Toes REM et al (2016) Viral persistence induces antibody inflation without altering antibody avidity. J Virol 90:4402–4411PubMedPubMedCentral

27.

Arens R, Loewendorf A, Her MJ et al (2011) B7-mediated costimulation of CD4 T cells constrains cytomegalovirus persistence. J Virol 85:390–396PubMed

28.

Humphreys IR, Loewendorf A, De Trez C et al (2007) OX40 costimulation promotes persistence of cytomegalovirus-specific CD8 T Cells: A CD4-dependent mechanism. J Immunol 179:2195–2202PubMed

29.

Humphreys IR, Lee SW, Jones M et al (2010) Biphasic role of 4-1BB in the regulation of mouse cytomegalovirus-specific CD8(+) T cells. Eur J Immunol 40:2762–2768PubMedPubMedCentral

30.

Snyder CM, Loewendorf A, Bonnett EL et al (2009) CD4+ T cell help has an epitope-dependent impact on CD8+ T cell memory inflation during murine cytomegalovirus infection. J Immunol 183:3932–3941PubMedPubMedCentral

31.

Walton SM, Torti N, Mandaric S et al (2011) T-cell help permits memory CD8(+) T-cell inflation during cytomegalovirus latency. Eur J Immunol 41:2248–2259PubMed

32.

Bachmann MF, Wolint P, Walton S et al (2007) Differential role of IL-2R signaling for CD8+ T cell responses in acute and chronic viral infections. Eur J Immunol 37:1502–1512PubMed

33.

Redeker A, Welten SP, Baert MR et al (2015) The quantity of autocrine IL-2 governs the expansion potential of CD8+ T Cells. J Immunol 195:4792–4801PubMed

34.

Snyder CM, Cho KS, Bonnett EL et al (2008) Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 29:650–659PubMedPubMedCentral

35.

Jonjic S, Mutter W, Weiland F et al (1989) Site-restricted persistent cytomegalovirus infection after selective long-term depletion of CD4+ T lymphocytes. J Exp Med 169:1199–1212PubMed

36.

Walton SM, Mandaric S, Torti N et al (2011) Absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells. PLoS Pathog 7:e1002214PubMedPubMedCentral

37.

Loewendorf AI, Arens R, Purton JF et al (2011) Dissecting the requirements for maintenance of the CMV-specific memory T-cell pool. Viral Immunol 24:351–355PubMedPubMedCentral

38.

Torti N, Walton SM, Brocker T et al (2011) Non-hematopoietic cells in lymph nodes drive memory CD8 T cell inflation during murine cytomegalovirus infection. PLoS Pathog 7:e1002313PubMedPubMedCentral

39.

Mercer JA, Wiley CA, Spector DH (1988) Pathogenesis of murine cytomegalovirus infection: identification of infected cells in the spleen during acute and latent infections. J Virol 62:987–997PubMedPubMedCentral

40.

Seckert CK, Renzaho A, Tervo HM et al (2009) Liver sinusoidal endothelial cells are a site of murine cytomegalovirus latency and reactivation. J Virol 83:8869–8884PubMedPubMedCentral

41.

Smith CJ, Turula H, Snyder CM (2014) Systemic hematogenous maintenance of memory inflation by MCMV infection. PLoS Pathog 10:e1004233PubMedPubMedCentral

42.

Reddehase MJ, Balthesen M, Rapp M et al (1994) The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease. J Exp Med 179:185–193PubMed

43.

Polic B, Hengel H, Krmpotic A et al (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188:1047–1054PubMedPubMedCentral

44.

Reddehase MJ, Simon CO, Seckert CK et al (2008) Murine model of cytomegalovirus latency and reactivation. Curr Top Microbiol 325:315–331

45.

Sims S, Bolinger B, Klenerman P (2015) Increasing inflationary T-cell responses following transient depletion of MCMV-specific memory T cells. Eur J Immunol 45:113–118PubMed

46.

Simon CO, Holtappels R, Tervo HM et al (2006) CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation. J Virol 80:10436–10456PubMedPubMedCentral

47.

Baumann NS, Torti N, Welten SPM et al (2018) Tissue maintenance of CMV-specific inflationary memory T cells by IL-15. PLoS Pathog 14:e1006993PubMedPubMedCentral

48.

Remmerswaal EB, Havenith SH, Idu MM et al (2012) Human virus-specific effector-type T cells accumulate in blood but not in lymph nodes. Blood 119:1702–1712PubMed

49.

Bachmann MF, Wolint P, Schwarz K et al (2005) Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor alpha and CD62L. J Immunol 175:4686–4696PubMed

50.

Quinn M, Turula H, Tandon M et al (2015) Memory T cells specific for murine cytomegalovirus re-emerge after multiple challenges and recapitulate immunity in various adoptive transfer scenarios. J Immunol 194:1726–1736PubMedPubMedCentral

51.

Gerlach C, Moseman EA, Loughhead SM et al (2016) The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45:1270–1284PubMedPubMedCentral

52.

Gordon CL, Lee LN, Swadling L et al (2018) Induction and maintenance of CX3CR1-intermediate peripheral memory CD8(+) T cells by persistent viruses and vaccines. Cell Rep 23:768–782PubMedPubMedCentral

53.

Klenerman P (2018) The (gradual) rise of memory inflation. Immunol Rev 283:99–112PubMedPubMedCentral

54.

Feau S, Arens R, Togher S et al (2011) Autocrine IL-2 is required for secondary population expansion of CD8(+) memory T cells. Nat Immunol 12:908–913PubMedPubMedCentral

55.

Farrington LA, Smith TA, Grey F et al (2013) Competition for antigen at the level of the APC is a major determinant of immunodominance during memory inflation in murine cytomegalovirus infection. J Immunol 190:3410–3416PubMedPubMedCentral

56.

Turula H, Smith CJ, Grey F et al (2013) Competition between T cells maintains clonal dominance during memory inflation induced by MCMV. Eur J Immunol 43:1252–1263PubMedPubMedCentral

57.

Griffiths SJ, Riddell NE, Masters J et al (2013) Age-associated increase of low-avidity cytomegalovirus-specific CD8+ T cells that re-express CD45RA. J Immunol 190:5363–5372PubMedPubMedCentral

58.

Almanan M, Raynor J, Sholl A et al (2017) Tissue-specific control of latent CMV reactivation by regulatory T cells. PLoS Pathog 13:e1006507PubMedPubMedCentral

59.

Jones M, Ladell K, Wynn KK et al (2010) IL-10 restricts memory T cell inflation during cytomegalovirus infection. J Immunol 185:3583–3592PubMedPubMedCentral

60.

Wiesel M, Crouse J, Bedenikovic G et al (2012) Type-I IFN drives the differentiation of short-lived effector CD8+ T cells in vivo. Eur J Immunol 42:320–329PubMed

61.

Joshi NS, Cui W, Chandele A et al (2007) Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27:281–295PubMedPubMedCentral

62.

Cui W, Joshi NS, Jiang A et al (2009) Effects of Signal 3 during CD8 T cell priming: bystander production of IL-12 enhances effector T cell expansion but promotes terminal differentiation. Vaccine 27:2177–2187PubMedPubMedCentral

63.

Thom JT, Weber TC, Walton SM et al (2015) The salivary gland acts as a sink for tissue-resident memory CD8(+) T cells, facilitating protection from local cytomegalovirus infection. Cell Rep 13:1125–1136PubMed

64.

Smith CJ, Caldeira-Dantas S, Turula H et al (2015) Murine CMV infection induces the continuous production of mucosal resident T cells. Cell Rep 13:1137–1148PubMedPubMedCentral

65.

Borkner L, Sitnik KM, Dekhtiarenko I et al (2017) Immune protection by a cytomegalovirus vaccine vector expressing a single low-avidity epitope. J Immunol 199:1737–1747PubMed

66.

Schenkel JM, Masopust D (2014) Tissue-resident memory T cells. Immunity 41:886–897PubMedPubMedCentral

67.

Takamura S (2017) Persistence in temporary lung niches: a survival strategy of lung-resident memory CD8(+) T cells. Viral Immunol 30:438–450PubMedPubMedCentral

68.

Welten SPM, Sandu I, Baumann NS et al (2018) Memory CD8 T cell inflation vs tissue-resident memory T cells: same patrollers, same controllers? Immunol Rev 283:161–175PubMed

69.

Tsuda Y, Caposio P, Parkins CJ et al (2011) A replicating cytomegalovirus-based vaccine encoding a single Ebola virus nucleoprotein CTL epitope confers protection against Ebola virus. PLoS Negl Trop Dis 5:e1275PubMedPubMedCentral

70.

Tsuda Y, Parkins CJ, Caposio P et al (2015) A cytomegalovirus-based vaccine provides long-lasting protection against lethal Ebola virus challenge after a single dose. Vaccine 33:2261–2266PubMedPubMedCentral

71.

Morabito KM, Ruckwardt TJ, Bar-Haim E et al (2018) Memory inflation drives tissue-resident memory CD8(+) T cell maintenance in the lung after intranasal vaccination with murine cytomegalovirus. Front Immunol 9:1861PubMedPubMedCentral

72.

Morabito KM, Ruckwardt TR, Redwood AJ et al (2017) Intranasal administration of RSV antigen-expressing MCMV elicits robust tissue-resident effector and effector memory CD8+ T cells in the lung. Mucosal Immunol 10:545–554PubMed

73.

Pizzolla A, Nguyen THO, Smith JM et al (2017) Resident memory CD8(+) T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci Immunol. https://doi.org/10.1126/sciimmunol.aam6970 CrossRefPubMed

74.

Slutter B, Van Braeckel-Budimir N, Abboud G et al (2017) Dynamics of influenza-induced lung-resident memory T cells underlie waning heterosubtypic immunity. Sci Immunol. https://doi.org/10.1126/sciimmunol.aag2031 CrossRefPubMedPubMedCentral

75.

Hansen SG, Vieville C, Whizin N et al (2009) Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 15:293–299PubMedPubMedCentral

76.

Hansen SG, Ford JC, Lewis MS et al (2011) Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine. Nature 473:523–527PubMedPubMedCentral

77.

Hansen SG, Piatak M Jr, Ventura AB et al (2013) Immune clearance of highly pathogenic SIV infection. Nature 502:100–104PubMedPubMedCentral

78.

Hansen SG, Wu HL, Burwitz BJ et al (2016) Broadly targeted CD8(+) T cell responses restricted by major histocompatibility complex E. Science 351:714–720PubMedPubMedCentral

79.

Klyushnenkova EN, Kouiavskaia DV, Parkins CJ et al (2012) A cytomegalovirus-based vaccine expressing a single tumor-specific CD8+ T-cell epitope delays tumor growth in a murine model of prostate cancer. J Immunother 35:390–399PubMedPubMedCentral

80.

Qiu Z, Huang H, Grenier JM et al (2015) Cytomegalovirus-based vaccine expressing a modified tumor antigen induces potent tumor-specific CD8(+) T-cell response and protects mice from melanoma. Cancer Immunol Res 3:536–546PubMed

81.

Erkes DA, Xu G, Daskalakis C et al (2016) Intratumoral infection with murine cytomegalovirus synergizes with PD-L1 blockade to clear melanoma lesions and induce long-term immunity. Mol Ther 24:1444–1455PubMedPubMedCentral

82.

Tierney R, Nakai T, Parkins CJ et al (2012) A single-dose cytomegalovirus-based vaccine encoding tetanus toxin fragment C induces sustained levels of protective tetanus toxin antibodies in mice. Vaccine 30:3047–3052PubMed

83.

Marzi A, Murphy AA, Feldmann F et al (2016) Cytomegalovirus-based vaccine expressing Ebola virus glycoprotein protects nonhuman primates from Ebola virus infection. Sci Rep 6:21674PubMedPubMedCentral

84.

Xu G, Smith T, Grey F et al (2013) Cytomegalovirus-based cancer vaccines expressing TRP2 induce rejection of melanoma in mice. Biochem Biophys Res Commun 437:287–291PubMedPubMedCentral

85.

Benonisson H, Sow HS, Breukel C et al (2018) FcgammaRI expression on macrophages is required for antibody-mediated tumor protection by cytomegalovirus-based vaccines. Oncotarget 9:29392–29402PubMedPubMedCentral

86.

Lee LN, Bolinger B, Banki Z et al (2017) Adenoviral vaccine induction of CD8+ T cell memory inflation: Impact of co-infection and infection order. PLoS Pathog 13:e1006782PubMedPubMedCentral

87.

Solana R, Tarazona R, Aiello AE et al (2012) CMV and immunosenescence: from basics to clinics. Immun Ageing 9:23PubMedPubMedCentral

88.

Redeker A, Remmerswaal EBM, Van Der Gracht ETI et al (2017) The contribution of cytomegalovirus infection to immune senescence is set by the infectious dose. Front Immunol 8:1953PubMed

89.

Bolinger B, Sims S, O’hara G et al (2013) A new model for CD8+ T cell memory inflation based upon a recombinant adenoviral vector. J Immunol 190:4162–4174PubMedPubMedCentral

90.

Bolinger B, Sims S, Swadling L et al (2015) Adenoviral vector vaccination induces a conserved program of CD8(+) T cell memory differentiation in mouse and man. Cell Rep 13:1578–1588PubMedPubMedCentral

91.

Gordon CL, Hutchings CL, Highton AJ et al (2018) Memory inflation following adenoviral vaccination depends on IL-21. Vaccine 36:7011–7016PubMedPubMedCentral

92.

Mclaren JE, Clement M, Marsden M et al (2019) IL-33 augments virus-specific memory T cell inflation and potentiates the efficacy of an attenuated cytomegalovirus-based vaccine. J Immunol 202:943–955PubMedPubMedCentral

93.

Trsan T, Vukovic K, Filipovic P et al (2017) Cytomegalovirus vector expressing RAE-1gamma induces enhanced anti-tumor capacity of murine CD8(+) T cells. Eur J Immunol 47:1354–1367PubMedPubMedCentral

94.

Hirsl L, Brizic I, Jenus T et al (2018) Murine CMV expressing the high affinity NKG2D ligand MULT-1: a model for the development of cytomegalovirus-based vaccines. Front Immunol 9:991PubMedPubMedCentral

Titel: Fuel and brake of memory T cell inflation
verfasst von: Suzanne P. M. Welten
Nicolas S. Baumann
Annette Oxenius
Publikationsdatum: 09.03.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: Medical Microbiology and Immunology / Ausgabe 3-4/2019
Print ISSN: 0300-8584
Elektronische ISSN: 1432-1831
DOI: https://doi.org/10.1007/s00430-019-00587-9

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