Abstract
CD4+ T helper cells regulate appropriate cellular and humoral immune responses to a wide range of pathogens and get involved in many diseases progress. The balance of the earliest determined CD4+ T helper cell subsets, Th1 and Th2, play an important role in allergy and autoimmune diseases. During the research, Animal models in immunology research are necessary and always the powerful tools for the basic scientific research. With the new sequence technologies, the finding of key gene mutation in Th1/Th2 cells has been proved to be related to human diseases. Here, we review four animal models about four key genes in Th1/Th2 cells to introduce the balance between Th1/Th2 cells. Furthermore, the related genetic mutations in human diseases and the new therapies are reviewed in this chapter, which show the importance of Th1/Th2 cells in human diseases further.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schaffer AA et al (2012) The phenotype of human STK4 deficiency. Blood 119:3450–3457
Aguayo S, Munoz MJ, de la Torre A, Roset J, de la Pena E, Carballo M (2004) Identification of organic compounds and ecotoxicological assessment of sewage treatment plants (STP) effluents. Sci Total Environ 328:69–81
Akahoshi M, Obara K, Hirota T, Matsuda A, Hasegawa K, Takahashi N et al (2005) Functional promoter polymorphism in the TBX21 gene associated with aspirin-induced asthma. Hum Genet 117:16–26
Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF et al (2007) Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: insight into mechanisms of DNA binding by the GATA3 transcription factor. Hum Mol Genet 16:265–275
Boisson-Dupuis S, Kong XF, Okada S, Cypowyj S, Puel A, Abel L et al (2012) Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol 24:364–378
Bour-Jordan H, Grogan JL, Tang Q, Auger JA, Locksley RM, Bluestone JA (2003) CTLA-4 regulates the requirement for cytokine-induced signals in T(H)2 lineage commitment. Nat Immunol 4:182–188
Bruton OC (1952) Agammaglobulinemia. Pediatrics 9:722–728
Casanova JL, Abel L (2007) Primary immunodeficiencies: a field in its infancy. Science 317:617–619
Chen H, Sun H, You F, Sun W, Zhou X, Chen L et al (2011) Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147:436–446
Cheung WL, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen CA et al (2003) Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell 113:507–517
Chiu WY, Chen HW, Chao HW, Yann LT, Tsai KS (2006) Identification of three novel mutations in the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. J Clin Endocrinol Metab 91:4587–4592
Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ et al (2009) Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 206:299–311
Copeland NG, Gilbert DJ, Schindler C, Zhong Z, Wen Z, Darnell JE Jr et al (1995) Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics 29:225–228
Copeland NG, Jenkins NA, Gilbert DJ, Eppig JT, Maltais LJ, Miller JC et al (1993) A genetic linkage map of the mouse: current applications and future prospects. Science 262:57–66
Cormier SA, Kolls JK (2011) Innate IL-13 in virus-induced asthma? Nat Immunol 12:587–588
Creasy CL, Chernoff J (1995) Cloning and characterization of a human protein kinase with homology to Ste20. J Biol Chem 270:21695–21700
Davis MM (2012) Immunology taught by humans. Sci Transl Med 4:117fs2
Duetsch G, Illig T, Loesgen S, Rohde K, Klopp N, Herbon N et al (2002) STAT6 as an asthma candidate gene: polymorphism-screening, association and haplotype analysis in a Caucasian sib-pair study. Hum Mol Genet 11:613–621
Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S, Harris J et al (2001) Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293:300–303
Eyerich K, Foerster S, Rombold S, Seidl HP, Behrendt H, Hofmann H et al (2008) Patients with chronic mucocutaneous candidiasis exhibit reduced production of Th17-associated cytokines IL-17 and IL-22. J Invest Dermatol 128:2640–2645
Ferraris S, Del Monaco AG, Garelli E, Carando A, De Vito B, Pappi P et al (2009) HDR syndrome: a novel “de novo” mutation in GATA3 gene. Am J Med Genet A 149A:770–775
Filipe-Santos O, Bustamante J, Chapgier A, Vogt G, de Beaucoudrey L, Feinberg J et al (2006) Inborn errors of IL-12/23- and IFN-gamma-mediated immunity: molecular, cellular, and clinical features. Semin Immunol 18:347–361
Finotto S, Neurath MF, Glickman JN, Qin S, Lehr HA, Green FH et al (2002) Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet. Science 295:336–338
Gao PS, Heller NM, Walker W, Chen CH, Moller M, Plunkett B et al (2004) Variation in dinucleotide (GT) repeat sequence in the first exon of the STAT6 gene is associated with atopic asthma and differentially regulates the promoter activity in vitro. J Med Genet 41:535–539
Gateva V, Sandling JK, Hom G, Taylor KE, Chung SA, Sun X et al (2009) A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet 41:1228–1233
Han JW, Zheng HF, Cui Y, Sun LD, Ye DQ, Hu Z et al (2009) Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus. Nat Genet 41:1234–1237
Hernandez AM, Villamar M, Rosello L, Moreno-Pelayo MA, Moreno F, Del Castillo I (2007) Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations. Am J Med Genet A 143:757–762
Hou J, Schindler U, Henzel WJ, Ho TC, Brasseur M, McKnight SL (1994) An interleukin-4-induced transcription factor: IL-4 Stat. Science 265:1701–1706
Jamieson RV, Perveen R, Kerr B, Carette M, Yardley J, Heon E et al (2002) Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma. Hum Mol Genet 11:33–42
Joulin V, Bories D, Eleouet JF, Labastie MC, Chretien S, Mattei MG et al (1991) A T-cell specific TCR delta DNA binding protein is a member of the human GATA family. EMBO J 10:1809–1816
Kariuki SN, Kirou KA, MacDermott EJ, Barillas-Arias L, Crow MK, Niewold TB (2009) Cutting edge: autoimmune disease risk variant of STAT4 confers increased sensitivity to IFN-alpha in lupus patients in vivo. J Immunol 182:34–38
Kaufman CK, Zhou P, Pasolli HA, Rendl M, Bolotin D, Lim KC et al (2003) GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev 17:2108–2122
Kim JI, Ho IC, Grusby MJ, Glimcher LH (1999) The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity 10:745–751
Kim JI, Li T, Ho IC, Grusby MJ, Glimcher LH (1999) Requirement for the c-Maf transcription factor in crystallin gene regulation and lens development. Proc Natl Acad Sci USA 96:3781–3785
Kirkpatrick CH (1994) Chronic mucocutaneous candidiasis. J Am Acad Dermatol 31:S14–S17
Kisand K, Boe Wolff AS, Podkrajsek KT, Tserel L, Link M, Kisand KV et al (2010) Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J Exp Med 207:299–308
Kong XF, Ciancanelli M, Al-Hajjar S, Alsina L, Zumwalt T, Bustamante J et al (2010) A novel form of human STAT1 deficiency impairing early but not late responses to interferons. Blood 116:5895–5906
Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z (2006) GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127:1041–1055
Kristensen IA, Veirum JE, Moller BK, Christiansen M (2011) Novel STAT1 alleles in a patient with impaired resistance to mycobacteria. J Clin Immunol 31:265–271
Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z et al (2002) Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med 8:885–889
Leek JP, Hamlin PJ, Bell SM, Lench NJ (1997) Assignment of the STAT6 gene (STAT6) to human chromosome band 12q13 by in situ hybridization. Cytogenet Cell Genet 79:208–209
Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB et al (2006) A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125:987–1001
Lim KC, Lakshmanan G, Crawford SE, Gu Y, Grosveld F, Engel JD (2000) Gata3 loss leads to embryonic lethality due to noradrenaline deficiency of the sympathetic nervous system. Nat Genet 25:209–212
Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A et al (2011) Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med 208:1635–1648
Lyon MF, Jamieson RV, Perveen R, Glenister PH, Griffiths R, Boyd Y et al (2003) A dominant mutation within the DNA-binding domain of the bZIP transcription factor Maf causes murine cataract and results in selective alteration in DNA binding. Hum Mol Genet 12:585–594
Moldovan O, Carvalho R, Jorge Z, and Medeira A (2011) A new case of HDR syndrome with severe female genital tract malformation: comment on “Novel mutation in the gene encoding the GATA3 transcription factor in a Spanish familial case of hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome with female genital tract malformations” by Hernandez et al. Am J Med Genet A 155A:2329–2330
Mou F, Praskova M, Xia F, Van Buren D, Hock H, Avruch J et al (2012) The Mst1 and Mst2 kinases control activation of rho family GTPases and thymic egress of mature thymocytes. J Exp Med 209:741–759
Mullen AC, Hutchins AS, High FA, Lee HW, Sykes KJ, Chodosh LA et al (2002) Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nat Immunol 3:652–658
Muroya K, Hasegawa T, Ito Y, Nagai T, Isotani H, Iwata Y et al (2001) GATA3 abnormalities and the phenotypic spectrum of HDR syndrome. J Med Genet 38:374–380
Nehme NT, Pachlopnik Schmid J, Debeurme F, Andre-Schmutz I, Lim A, Nitschke P et al (2012) MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119:3458–3468
Nesbit MA, Bowl MR, Harding B, Ali A, Ayala A, Crowe C et al (2004) Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem 279:22624–22634
Nishizawa M, Kataoka K, Goto N, Fujiwara KT, Kawai S (1989) v-maf, a viral oncogene that encodes a “leucine zipper” motif. Proc Natl Acad Sci USA 86:7711–7715
Ochs HD, Hitzig WH (2012) History of primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol 12:577–587
Pai SY, Truitt ML, Ting CN, Leiden JM, Glimcher LH, Ho IC (2003) Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19:863–875
Pandolfi PP, Roth ME, Karis A, Leonard MW, Dzierzak E, Grosveld FG et al (1995) Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 11:40–44
Patel BK, Pierce JH, LaRochelle WJ (1998) Regulation of interleukin 4-mediated signaling by naturally occurring dominant negative and attenuated forms of human Stat6. Proc Natl Acad Sci USA 95:172–177
Perveen R, Favor J, Jamieson RV, Ray DW, Black GC (2007) A heterozygous c-Maf transactivation domain mutation causes congenital cataract and enhances target gene activation. Hum Mol Genet 16:1030–1038
Puel A, Cypowyj S, Bustamante J, Wright JF, Liu L, Lim HK et al (2011) Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332:65–68
Puel A, Doffinger R, Natividad A, Chrabieh M, Barcenas-Morales G, Picard C et al (2010) Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I. J Exp Med 207:291–297
Quelle FW, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben SM et al (1995) Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol 15:3336–3343
Ravindran R, Foley J, Stoklasek T, Glimcher LH, McSorley SJ (2005) Expression of T-bet by CD4 T cells is essential for resistance to Salmonella infection. J Immunol 175:4603–4610
Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW et al (2007) STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 357:977–986
Ring BZ, Cordes SP, Overbeek PA, Barsh GS (2000) Regulation of mouse lens fiber cell development and differentiation by the Maf gene. Development 127:307–317
Romberg N, Morbach H, Lawrence MG, Kim S, Kang I, Holland SM et al (2013) Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival. J Allergy Clin Immunol 131:1691–1693
Rosen MJ, Chaturvedi R, Washington MK, Kuhnhein LA, Moore PD, Coggeshall SS et al (2013) STAT6 deficiency ameliorates severity of oxazolone colitis by decreasing expression of claudin-2 and Th2-inducing cytokines. J Immunol 190:1849–1858
Sampaio EP, Hsu AP, Pechacek J, Bax HI, Dias DL, Paulson ML et al (2013) Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol 131:1624–1634 248
Sasaki Y, Ihara K et al (2004) Identification of a novel type 1 diabetes susceptibility gene, T-bet. Hum Genet 115(3):177–184
Smeekens SP, Plantinga TS, van de Veerdonk FL, Heinhuis B, Hoischen A, Joosten LA et al (2011) STAT1 hyperphosphorylation and defective IL12R/IL23R signaling underlie defective immunity in autosomal dominant chronic mucocutaneous candidiasis. PLoS ONE 6:e29248
Svaren J, Apel ED, Simburger KS, Jenkins NA, Gilbert DJ, Copeland NA et al (1997) The Nab2 and Stat6 genes share a common transcription termination region. Genomics 41:33–39
Svensson A, Nordstrom I, Sun JB, Eriksson K (2005) Protective immunity to genital herpes simplex [correction of simpex] virus type 2 infection is mediated by T-bet. J Immunol 174:6266–6273
Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669
Taylor LK, Wang HC, Erikson RL (1996) Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci USA 93:10099–10104
Uzel G, Sampaio EP, Lawrence MG, Hsu AP, Hackett M, Dorsey MJ et al (2013) Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome. J Allergy Clin Immunol 131:1611–1623
van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C et al (2011) STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med 365:54–61
van der Graaf CA, Netea MG, Drenth IP, te Morsche RH, van der Meer JW, Kullberg BJ (2003) Candida-specific interferon-gamma deficiency and toll-like receptor polymorphisms in patients with chronic mucocutaneous candidiasis. Neth J Med 61:365–369
Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G et al (2000) GATA3 haplo-insufficiency causes human HDR syndrome. Nature 406:419–422
Wang J, Fathman JW, Lugo-Villarino G, Scimone L, von Andrian U, Dorfman DM et al (2006) Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells. J Clin Invest 116:414–421
Wang W, Ostlie NS, Conti-Fine BM, Milani M (2004) The susceptibility to experimental myasthenia gravis of STAT6−/− and STAT4−/− BALB/c mice suggests a pathogenic role of Th1 cells. J Immunol 172:97–103
Weidinger S, Klopp N, Wagenpfeil S, Rummler L, Schedel M, Kabesch M et al (2004) Association of a STAT 6 haplotype with elevated serum IgE levels in a population based cohort of white adults. J Med Genet 41:658–663
Wende H, Lechner SG, Cheret C, Bourane S, Kolanczyk ME, Pattyn A et al (2012) The transcription factor c-Maf controls touch receptor development and function. Science 335:1373–1376
Yamamoto K, Kobayashi H, Arai A, Miura O, Hirosawa S, Miyasaka N (1997) cDNA cloning, expression and chromosome mapping of the human STAT4 gene: both STAT4 and STAT1 genes are mapped to 2q32.2-->q32.3. Cytogenet Cell Genet 77:207–210
Zhang DH, Cohn L, Ray P, Bottomly K, Ray A (1997) Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem 272:21597–21603
Zhang WX, Yang SY (2000) Cloning and characterization of a new member of the T-box gene family. Genomics 70:41–48
Zheng W, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596
Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q et al (2004) Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol 5:1157–1165
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Zhang, Y., Zhang, Y., Gu, W., He, L., Sun, B. (2014). Th1/Th2 Cell’s Function in Immune System. In: Sun, B. (eds) T Helper Cell Differentiation and Their Function. Advances in Experimental Medicine and Biology, vol 841. Springer, Dordrecht. https://doi.org/10.1007/978-94-017-9487-9_3
Download citation
DOI: https://doi.org/10.1007/978-94-017-9487-9_3
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-017-9486-2
Online ISBN: 978-94-017-9487-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)