Skip to main content
SpringerLink
Log in
Book cover

T-Cell Differentiation pp 19–30Cite as

Basic Aspects of T Helper Cell Differentiation

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1514))

Abstract

CD4+ T helper cells orchestrate the immune response and play a pivotal role during infection, chronic inflammatory, autoimmune diseases, and carcinogenesis. CD4+ T helper cells can be subdivided into different subsets, which are characterized by a specific network of transcriptional regulators and unique cytokine profiles: Th17 cells express RORγt that in turn promotes the transcription of Il17a, Il17f; Th1 cells, expresses T-bet and produces IFN-γ, IL-2, and TNF-α; Th2 cells express GATA-3 and secrete IL-4, IL-5, and IL-13. The two most studied regulatory T cell subtypes are Foxp3+ regulatory T cells, which can be generated either in the thymus (tTreg) or induced in peripheral lymphoid organs (pTregs) and type 1 regulatory T cells (Tr1), which are induced in the periphery. These T helper cell subsets can be differentiated from naïve T cells. In addition, recent findings indicate that some T helper cell subsets can emerge from other T helper cells, suggesting a certain degree of plastiticy. Here we report basic aspects of T helper cell differentiation and function while underlining some still open questions.

This is a preview of subscription content, log in via an institution.

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   139.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   159.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 28:445–489. doi:10.1146/annurev-immunol-030409-101212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136(7):2348–2357

    CAS  PubMed  Google Scholar 

  3. Reiner SL, Adams WC (2014) Lymphocyte fate specification as a deterministic but highly plastic process. Nat Rev Immunol 14(10):699–704. doi:10.1038/nri3734

    Article  CAS  PubMed  Google Scholar 

  4. Hsieh CS, Macatonia SE, Tripp CS et al (1993) Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260(5107):547–549

    Article  CAS  PubMed  Google Scholar 

  5. Usui T, Preiss JC, Kanno Y et al (2006) T-bet regulates Th1 responses through essential effects on GATA-3 function rather than on IFNG gene acetylation and transcription. J Exp Med 203(3):755–766. doi:10.1084/jem.20052165, jem.20052165 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Usui T, Nishikomori R, Kitani A, Strober W (2003) GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rbeta2 chain or T-bet. Immunity 18(3):415–428. doi:10.1016/S1074-7613(03)00057-8, S1074761303000578 [pii]

    Article  CAS  PubMed  Google Scholar 

  7. Szabo SJ, Kim ST, Costa GL et al (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100(6):655–669. doi:10.1016/S0092-8674(00)80702-3, S0092-8674(00)80702-3 [pii]

    Article  CAS  PubMed  Google Scholar 

  8. Szabo SJ, Sullivan BM, Stemmann C et al (2002) Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295(5553):338–342. doi:10.1126/science.1065543, 295/5553/338 [pii]

    Article  CAS  PubMed  Google Scholar 

  9. Wei G, Wei L, Zhu J et al (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30(1):155–167. doi:10.1016/j.immuni.2008.12.009

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Panzer M, Sitte S, Wirth S et al (2012) Rapid in vivo conversion of effector T cells into Th2 cells during helminth infection. J Immunol 188(2):615–623. doi:10.4049/jimmunol.1101164

    Article  CAS  PubMed  Google Scholar 

  11. Becattini S, Latorre D, Mele F et al (2015) T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines. Science 347(6220):400–406. doi:10.1126/science.1260668

    Article  CAS  PubMed  Google Scholar 

  12. Clemente-Casares X, Blanco J, Ambalavanan P, Yamanouchi J, Singha S, Fandos C, Tsai S, Wang J, Garabatos N, Izquierdo C, Agrawal S, Keough MB, Yong VW, James E, Moore A, Yang Y, Stratmann T, Serra P, Santamaria P (2016) Expanding antigenspecific regulatory networks to treat autoimmunity. Nature 530(7591):434–40. doi:10.1038/nature16962, Epub 2016 Feb 17

    Article  CAS  PubMed  Google Scholar 

  13. Saraiva M, Christensen JR, Veldhoen M et al (2009) Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31(2):209–219. doi:10.1016/j.immuni.2009.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Le Gros G, Ben-Sasson SZ, Seder R, Finkelman FD, Paul WE (1990) Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med 172(3):921–929

    Article  PubMed  Google Scholar 

  15. Seder RA, Boulay JL, Finkelman F et al (1992) CD8+ T cells can be primed in vitro to produce IL-4. J Immunol 148(6):1652–1656

    CAS  PubMed  Google Scholar 

  16. Swain SL, Weinberg AD, English M, Huston G (1990) IL-4 directs the development of Th2-like helper effectors. J Immunol 145(11):3796–3806

    CAS  PubMed  Google Scholar 

  17. Kaplan MH, Schindler U, Smiley ST, Grusby MJ (1996) Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4(3):313–319, doi:S1074-7613(00)80439-2 [pii]

    Article  CAS  PubMed  Google Scholar 

  18. Shimoda K, van Deursen J, Sangster MY et al (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380(6575):630–633. doi:10.1038/380630a0

    Article  CAS  PubMed  Google Scholar 

  19. Takeda K, Tanaka T, Shi W et al (1996) Essential role of Stat6 in IL-4 signalling. Nature 380(6575):627–630. doi:10.1038/380627a0

    Article  CAS  PubMed  Google Scholar 

  20. Kurata H, Lee HJ, O'Garra A, Arai N (1999) Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Immunity 11(6):677–688. doi:10.1016/S1074-7613(00)80142-9, S1074-7613(00)80142-9 [pii]

    Article  CAS  PubMed  Google Scholar 

  21. Zhu J, Guo L, Watson CJ, Hu-Li J, Paul WE (2001) Stat6 is necessary and sufficient for IL-4's role in Th2 differentiation and cell expansion. J Immunol 166(12):7276–7281

    Article  CAS  PubMed  Google Scholar 

  22. 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(4):587–596. doi:10.1016/S0092-8674(00)80240-8, S0092-8674(00)80240-8 [pii]

    Article  CAS  PubMed  Google Scholar 

  23. 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(34):21597–21603

    Article  CAS  PubMed  Google Scholar 

  24. Zhu J, Min B, Hu-Li J et al (2004) Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol 5(11):1157–1165. doi:10.1038/ni1128, ni1128 [pii]

    Article  CAS  PubMed  Google Scholar 

  25. Zhu J, Cote-Sierra J, Guo L, Paul WE (2003) Stat5 activation plays a critical role in Th2 differentiation. Immunity 19(5):739–748. doi:10.1016/S1074-7613(03)00292-9, S1074761303002929 [pii]

    Article  CAS  PubMed  Google Scholar 

  26. Bruchard M, Rebe C, Derangere V et al (2015) The receptor NLRP3 is a transcriptional regulator of TH2 differentiation. Nat Immunol 16(8):859–870. doi:10.1038/ni.3202

    Article  CAS  PubMed  Google Scholar 

  27. Wu L, Zepp JA, Qian W et al (2015) A novel IL-25 signaling pathway through STAT5. J Immunol 194(9):4528–4534. doi:10.4049/jimmunol.1402760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hegazy AN, Peine M, Helmstetter C et al (2010) Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity 32(1):116–128. doi:10.1016/j.immuni.2009.12.004

    Article  CAS  PubMed  Google Scholar 

  29. Coomes SM, Pelly VS, Kannan Y et al (2015) IFNgamma and IL-12 Restrict Th2 Responses during Helminth/Plasmodium Co-Infection and Promote IFNgamma from Th2 Cells. PLoS Pathog 11(7):e1004994. doi:10.1371/journal.ppat.1004994

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Kim BS, Kim IK, Park YJ et al (2010) Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma. Proc Natl Acad Sci U S A 107(19):8742–8747. doi:10.1073/pnas.0911756107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Conti HR, Shen F, Nayyar N et al (2009) Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 206(2):299–311. doi:10.1084/jem.20081463, jem.20081463 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang W, Na L, Fidel PL, Schwarzenberger P (2004) Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice. J Infect Dis 190(3):624–631

    Article  CAS  PubMed  Google Scholar 

  33. Ye P, Garvey PB, Zhang P et al (2001) Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol 25(3):335–340

    Article  CAS  PubMed  Google Scholar 

  34. Iwakura Y, Nakae S, Saijo S, Ishigame H (2008) The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev 226:57–79. doi:10.1111/j.1600-065X.2008.00699.x, IMR699 [pii]

    Article  CAS  PubMed  Google Scholar 

  35. Ishigame H, Kakuta S, Nagai T et al (2009) Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30(1):108–119. doi:10.1016/j.immuni.2008.11.009, S1074-7613(08)00554-2 [pii]

    Article  CAS  PubMed  Google Scholar 

  36. Atarashi K, Tanoue T, Ando M et al (2015) Th17 cell induction by adhesion of microbes to intestinal epithelial cells. Cell 163(2):367–380. doi:10.1016/j.cell.2015.08.058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ling Y, Cypowyj S, Aytekin C et al (2015) Inherited IL-17RC deficiency in patients with chronic mucocutaneous candidiasis. J Exp Med 212(5):619–631. doi:10.1084/jem.20141065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou L, Ivanov II, Spolski R et al (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8(9):967–974

    Article  CAS  PubMed  Google Scholar 

  39. Nurieva R, Yang XO, Martinez G et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152):480–483

    Article  CAS  PubMed  Google Scholar 

  40. Yang XO, Panopoulos AD, Nurieva R et al (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282(13):9358–9363

    Article  CAS  PubMed  Google Scholar 

  41. Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441(7090):235–238

    Article  CAS  PubMed  Google Scholar 

  42. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189

    Article  CAS  PubMed  Google Scholar 

  43. Ivanov II, McKenzie BS, Zhou L et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126(6):1121–1133

    Article  CAS  PubMed  Google Scholar 

  44. Mangan PR, Harrington LE, O'Quinn DB et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441(7090):231–234

    Article  CAS  PubMed  Google Scholar 

  45. McGeachy MJ, Chen Y, Tato CM et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10(3):314–324. doi:10.1038/ni.1698, ni.1698 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ahern PP, Schiering C, Buonocore S et al (2010) Interleukin-23 drives intestinal inflammation through direct activity on T cells. Immunity 33(2):279–288. doi:10.1016/j.immuni.2010.08.010, S1074-7613(10)00293-1 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sano T, Huang W, Hall JA et al (2015) An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 163(2):381–393. doi:10.1016/j.cell.2015.08.061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zielinski CE, Mele F, Aschenbrenner D, Jarrossay D, Ronchi F, Gattorno M, Monticelli S, Lanzavecchia A, Sallusto F (2012) Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1beta. Nature 484(7395):514–8. doi:10.1038/nature10957

  49. Shaw MH, Kamada N, Kim YG, Nunez G (2012) Microbiota-induced IL-1beta, but not IL-6, is critical for the development of steady-state TH17 cells in the intestine. J Exp Med 209(2):251–258. doi:10.1084/jem.20111703, jem.20111703 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ciofani M, Madar A, Galan C et al (2012) A validated regulatory network for Th17 cell specification. Cell 151(2):289–303. doi:10.1016/j.cell.2012.09.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yosef N, Shalek AK, Gaublomme JT et al (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496(7446):461–468. doi:10.1038/nature11981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang C, Yosef N, Gaublomme J et al (2015) CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163(6):1413–1427. doi:10.1016/j.cell.2015.10.068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gaublomme JT, Yosef N, Lee Y et al (2015) Single-cell genomics unveils critical regulators of Th17 cell pathogenicity. Cell 163(6):1400–1412. doi:10.1016/j.cell.2015.11.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Yu X, Rollins D, Ruhn KA et al (2013) TH17 cell differentiation is regulated by the circadian clock. Science 342(6159):727–730. doi:10.1126/science.1243884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Farez MF, Mascanfroni ID, Mendez-Huergo SP et al (2015) Melatonin contributes to the seasonality of multiple sclerosis relapses. Cell 162(6):1338–1352. doi:10.1016/j.cell.2015.08.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ghoreschi K, Laurence A, Yang XP et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467(7318):967–971. doi:10.1038/nature09447, nature09447 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. McGeachy MJ, Bak-Jensen KS, Chen Y et al (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397. doi:10.1038/ni1539, ni1539 [pii]

    Article  CAS  PubMed  Google Scholar 

  58. Gagliani N, Vesely MC, Iseppon A et al (2015) Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523(7559):221–225. doi:10.1038/nature14452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hirota K, Duarte JH, Veldhoen M et al (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12(3):255–263. doi:10.1038/ni.1993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hirota K, Turner JE, Villa M et al (2013) Plasticity of Th17 cells in Peyer’s patches is responsible for the induction of T cell-dependent IgA responses. Nat Immunol 14(4):372–379. doi:10.1038/ni.2552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Obermajer N, Popp FC, Soeder Y et al (2014) Conversion of Th17 into IL-17A(neg) regulatory T cells: a novel mechanism in prolonged allograft survival promoted by mesenchymal stem cell-supported minimized immunosuppressive therapy. J Immunol 193(10):4988–4999. doi:10.4049/jimmunol.1401776

    Article  CAS  PubMed  Google Scholar 

  62. Harbour SN, Maynard CL, Zindl CL, Schoeb TR, Weaver CT (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112(22):7061–7066. doi:10.1073/pnas.1415675112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 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(3):1151–1164

    CAS  PubMed  Google Scholar 

  64. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336

    Article  CAS  PubMed  Google Scholar 

  65. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061

    Article  CAS  PubMed  Google Scholar 

  66. Wan YY, Flavell RA (2007) Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445(7129):766–770

    Article  CAS  PubMed  Google Scholar 

  67. Passerini L, Santoni de Sio FR, Roncarolo MG, Bacchetta R (2014) Forkhead box P3: the peacekeeper of the immune system. Int Rev Immunol 33(2):129–145. doi:10.3109/08830185.2013.863303

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  69. Huber S, Schramm C, Lehr HA et al (2004) Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 173(11):6526–6531

    Article  CAS  PubMed  Google Scholar 

  70. Schramm C, Huber S, Protschka M et al (2004) TGFbeta regulates the CD4+CD25+ T-cell pool and the expression of Foxp3 in vivo. Int Immunol 16(9):1241–1249. doi:10.1093/intimm/dxh126, dxh126 [pii]

    Article  CAS  PubMed  Google Scholar 

  71. Fantini MC, Becker C, Monteleone G et al (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172(9):5149–5153

    Article  CAS  PubMed  Google Scholar 

  72. Chen W, Jin W, Hardegen N et al (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Kretschmer K, Apostolou I, Hawiger D et al (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6(12):1219–1227

    Article  CAS  PubMed  Google Scholar 

  74. Marie JC, Letterio JJ, Gavin M, Rudensky AY (2005) TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 201(7):1061–1067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bennett CL, Christie J, Ramsdell F et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21

    Article  CAS  PubMed  Google Scholar 

  76. Brunkow ME, Jeffery EW, Hjerrild KA 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(1):68–73

    Article  CAS  PubMed  Google Scholar 

  77. Huber S, Gagliani N, Esplugues E et al (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3- and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34(4):554–565. doi:10.1016/j.immuni.2011.01.020, S1074-7613(11)00129-4 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Fahlen L, Read S, Gorelik L et al (2005) T cells that cannot respond to TGF-{beta} escape control by CD4+CD25+ regulatory T cells. J Exp Med 201(5):737–746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Annunziato F, Cosmi L, Liotta F et al (2002) Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes. J Exp Med 196(3):379–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bopp T, Becker C, Klein M et al (2007) Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med 204(6):1303–1310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Hori S (2014) Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells. Immunol Rev 259(1):159–172. doi:10.1111/imr.12175

    Article  CAS  PubMed  Google Scholar 

  82. Haringer B, Lozza L, Steckel B, Geginat J (2009) Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood. J Exp Med 206(5):1009–1017. doi:10.1084/jem.20082238, jem.20082238 [pii]

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Roncarolo MG, Gregori S, Battaglia M et al (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50. doi:10.1111/j.0105-2896.2006.00420.x, IMR420 [pii]

    Article  CAS  PubMed  Google Scholar 

  84. Cobbold SP, Nolan KF, Graca L et al (2003) Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms. Immunol Rev 196:109–124, doi: 078 [pii]

    Article  CAS  PubMed  Google Scholar 

  85. Gagliani N, Jofra T, Stabilini A et al (2010) Antigen-specific dependence of Tr1-cell therapy in preclinical models of islet transplant. Diabetes 59(2):433–439. doi:10.2337/db09-1168, db09-1168 [pii]

    Article  CAS  PubMed  Google Scholar 

  86. Pestka S, Krause CD, Sarkar D et al (2004) Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 22:929–979. doi:10.1146/annurev.immunol.22.012703.104622

    Article  CAS  PubMed  Google Scholar 

  87. Cavani A, Nasorri F, Prezzi C et al (2000) Human CD4+ T lymphocytes with remarkable regulatory functions on dendritic cells and nickel-specific Th1 immune responses. J Invest Dermatol 114(2):295–302. doi:10.1046/j.1523-1747.2000.00881.x, jid881 [pii]

    Article  CAS  PubMed  Google Scholar 

  88. Strobl H, Emshoff R, Rothler G (1999) Conservative treatment of unilateral condylar fractures in children: a long-term clinical and radiologic follow-up of 55 patients. Int J Oral Maxillofac Surg 28(2):95–98

    Article  CAS  PubMed  Google Scholar 

  89. Cerwenka A, Swain SL (1999) TGF-beta1: immunosuppressant and viability factor for T lymphocytes. Microbes Infect 1(15):1291–1296, doi:S1286-4579(99)00255-5 [pii]

    Article  CAS  PubMed  Google Scholar 

  90. Groux H, O'Garra A, Bigler M et al (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737–742

    Article  CAS  PubMed  Google Scholar 

  91. Levings MK, Gregori S, Tresoldi E et al (2005) Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105(3):1162–1169. doi:10.1182/blood-2004-03-1211, 2004-03-1211 [pii]

    Article  CAS  PubMed  Google Scholar 

  92. Gregori S, Tomasoni D, Pacciani V et al (2010) Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 116(6):935–944. doi:10.1182/blood-2009-07-234872, blood-2009-07-234872 [pii]

    Article  CAS  PubMed  Google Scholar 

  93. Grossman WJ, Verbsky JW, Tollefsen BL et al (2004) Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104(9):2840–2848. doi:10.1182/blood-2004-03-0859, 2004-03-0859 [pii]

    Article  CAS  PubMed  Google Scholar 

  94. Grossman WJ, Verbsky JW, Barchet W et al (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21(4):589–601

    Article  CAS  PubMed  Google Scholar 

  95. Magnani CF, Alberigo G, Bacchetta R et al (2011) Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol 41(6):1652–1662. doi:10.1002/eji.201041120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Gagliani N, Magnani CF, Huber S et al (2013) Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med 19(6):739–746. doi:10.1038/nm.3179

    Article  CAS  PubMed  Google Scholar 

  97. Heinemann C, Heink S, Petermann F et al (2014) IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1. Nat Commun 5:3770. doi:10.1038/ncomms4770

    Article  CAS  PubMed  Google Scholar 

  98. Bacchetta R, Lucarelli B, Sartirana C et al (2014) Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol 5:16. doi:10.3389/fimmu.2014.00016

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Mascanfroni ID, Takenaka MC, Yeste A et al (2015) Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat Med 21(6):638–646. doi:10.1038/nm.3868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Okamura T, Fujio K, Shibuya M et al (2009) CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2. Proc Natl Acad Sci U S A 106(33):13974–13979. doi:10.1073/pnas.0906872106, 0906872106 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Facciotti F, Gagliani N, Haringer B et al (2015) IL-10-producing forkhead box protein 3-negative regulatory T cells inhibit B-cell responses and are involved in systemic lupus erythematosus. J Allergy Clin Immunol 137(1):318–321. doi:10.1016/j.jaci.2015.06.044

    Article  PubMed  CAS  Google Scholar 

  102. Burton BR, Britton GJ, Fang H et al (2014) Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy. Nat Commun 5:4741. doi:10.1038/ncomms5741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Apetoh L, Quintana FJ, Pot C et al (2010) The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat Immunol 11(9):854–861. doi:10.1038/ni.1912, ni.1912 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Vieira PL, Christensen JR, Minaee S et al (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol 172(10):5986–5993

    Article  CAS  PubMed  Google Scholar 

  105. Maynard CL, Harrington LE, Janowski KM et al (2007) Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nat Immunol 8(9):931–941. doi:10.1038/ni1504, ni1504 [pii]

    Article  CAS  PubMed  Google Scholar 

  106. Passerini L, Di Nunzio S, Gregori S et al (2011) Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol 41(4):1120–1131. doi:10.1002/eji.201040909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Iwasaki Y, Fujio K, Okamura T et al (2013) Egr-2 transcription factor is required for Blimp-1-mediated IL-10 production in IL-27-stimulated CD4+ T cells. Eur J Immunol 43(4):1063–1073. doi:10.1002/eji.201242942

    Article  CAS  PubMed  Google Scholar 

  108. Pot C, Apetoh L, Awasthi A, Kuchroo VK (2010) Molecular pathways in the induction of interleukin-27-driven regulatory type 1 cells. J Interferon Cytokine Res 30(6):381–388. doi:10.1089/jir.2010.0047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Nicola Gagliani

  2. I Medical Department, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246, Hamburg, Germany

    Nicola Gagliani & Samuel Huber

Authors
  1. Nicola Gagliani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Samuel Huber
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Samuel Huber .

Editor information

Editors and Affiliations

  1. Laboratory of Translational Immunology, Humanitas Clinical & Research Center, Rozzano, Italy

    Enrico Lugli

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer Science+Business Media New York

About this protocol

Cite this protocol

Gagliani, N., Huber, S. (2017). Basic Aspects of T Helper Cell Differentiation. In: Lugli, E. (eds) T-Cell Differentiation. Methods in Molecular Biology, vol 1514. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-6548-9_2

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-6548-9_2

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-6546-5

  • Online ISBN: 978-1-4939-6548-9

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation