T Lymphocytes: Helpers

Izumi Kawachi, Niigata University, Chuo‐ku, Niigata, Japan
Takayuki Kondo, Medical Research Institute, Kita‐ku, Osaka, Japan

Published online: December 2009

DOI: 10.1002/9780470015902.a0001224.pub2

Helper T lymphocytes are major histocompatibility complex (MHC) class II restricted CD4+ T cells which can be divided into several subsets of cytokine releasing patterns: T-helper 1 (TH1), T-helper 2 (TH2), T-helper 17 (TH-17) and T-follicular helper (TFH). Following are several transcription factors especially expressed, or function differently, in each of the clonal progeny to define separable effector T-helper cell lineages. Helper T cells orchestrate antibody production and cellular immune responses. TH1 cells activate infected macrophages for the destruction of intracellular pathogens. TH2 and TFH cells provide help to B cells for antibody production, which is a response aimed mainly at extracellular pathogens. TH-17 cells enhance neutrophil response for extracellular pathogens. Each TH subset plays a distinct role in host defence and autoimmunity.

Key concepts

  • Helper T lymphocytes are MHC class II restricted CD4+ T cells which can be divided into several subsets of cytokine releasing patterns: T-helper 1 (TH1), T-helper 2 (TH2), T-helper 17 (TH-17) and T-follicular helper (TFH).
  • IFN, IL-4 and IL-17 are the representative cytokines of TH1, TH2 and TH-17 cells, respectively, and are often used as subtype markers.
  • TH1 cells play an important role in cellular immune functions such as delayed-type hypersensitivity or in the defence against intracellular organisms.
  • TH2 cells enhance antibody production from B cells.
  • TH-17 cells are potent inducers of tissue inflammation in autoimmune diseases and confer protection against extracellular bacterial and fungal pathogens.
  • TFH cells regulate the step-wise development of antigen-specific B-cell immunity in B-cell follicles of lymphoid tissues.

Keywords: MHC class II; CD4; T-helper 1/T-helper 2/T-helper 17/regulatory T/T-follicular helper; antibody production

Figure 1. Lineage choices of T-helper cells in mice. The progeny of antigen experienced CD4+ T cells exposed to specific pathogen-associated signals, especially cytokines, can develop into T-helper 1 (TH1), T-helper 2 (TH2), T-helper 17 (TH-17), regulatory T (Treg) and follicular helper T (TFH) effector cells that can migrate to tissue. The critical transcription factors, T-bet for TH1, GATA-3 for TH2 and RORt for TH-17, as well as other lineage specific factors, IL-12R for TH1, Gfi-1 for TH2 and IL23R for TH-17, direct lineage commitment of each subset. Polarized T cells produce different sets of cytokines, and TH1, TH2 and TH-17 crossregulate each other by the cytokine they produce. Moreover, IL-21 feeds back on developing TH-17 cells, amplifying their frequency, as do IFN and IL-4 in the differentiation of TH1 and TH2 cells, respectively. APC, antigen-presenting cell; IL, interleukin; IFN, interferon ; LT, lymphotoxin; TNF, tumour necrosis factor and TGF, transforming growth factor .
Figure 2. Signalling pathways in TH1, Treg and TH-17 cell differentiation. Following engagement of the T-cell receptor, cytokines shape T-cell lineage commitment including TH1, TH2, TH-17 and Treg cells. The specific cytokines, their receptors and STAT transcription factors contribute to this intricate differentiation process.
Figure 3. (a) Helper T cells recognize processed antigen peptides and are activated. The specific interaction of an antigen-binding B cell with an armed helper T cell leads to the expression of the B-cell stimulatory molecule CD40 ligand on the helper T-cell surface and to the secretion of the B-cell stimulatory cytokines IL-4, IL-5, IL-6 or IL-21, which drive the proliferation and differentiation of the B cell into antibody-secreting plasma cells. Alternatively, an activated B cell can become a memory cell. (b) Many surface molecules are involved in T cell–B cell interaction. The first event is the T-cell receptor (TCR) and CD4 engagement of the peptide-MHC complex. This leads to expression of CD40L on T cells, and then the CD40/CD40L interaction causes upregulation of B7 costimulatory ligands on antigen-presenting cells (APC). The CD40 signal is critical for activating B cells. Signals from TCRs (CD40L) and CD28 activate T cells. CD2 on T cells and MHC on B cells can potentially also serve as costimulatory molecules as well as strengthen adhesion interactions. The B-cell stimulatory cytokines IL-4, IL-5, IL-6 or IL-21 are released at the point of contact, and drive the proliferation of differentiation of the B cell into antibody-secreting plasma cells.
Figure 4. Helper T cells produce macrophage-activating factors such as IFN and upregulate CD40 ligand (CD40L), followed by recognition of bacterial peptides-MHC class II on infected macrophages. IFN, interferon ; GM-CSF, granulocyte–macrophage colony-stimulating factor and TNF, tumour necrosis factor .
Figure 5. The models of helper function of CD4 T cells for CD8 cytotoxic T-cell responses.
close
 References
    Acosta-Rodriguez EV, Rivino L, Geginat J et al. (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nature Immunology 8: 639–646.
    Annunziato F, Cosmi L, Santarlasci V et al. (2007) Phenotypic and functional features of human TH-17 cells. Journal of Experimental Medicine 204: 1849–1861.
    Austrup F, Vestweber D, Borges E et al. (1997) P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 385: 81–83.
    Awasthi A, Carrier Y, Peron JP et al. (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nature Immunology 8: 1380–1389.
    Battaglia M, Gregori S, Bacchetta R et al. (2006) Tr1 cells: from discovery to their clinical application. Seminar in Immunology 18: 120–127.
    Bennett SR, Carbone FR, Karamalis F et al. (1998) Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393: 478–480.
    Bettelli E, Carrier Y, Gao W et al. (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH-17 and regulatory T cells. Nature 441: 235–238.
    Bevan MJ (2004) Helping the CD8+ T-cell response. Nature Reviews Immunology 4: 595–602.
    Bourgeois C, Rocha B and Tanchot C (2002) A role for CD40 expression on CD8+ T cells in the generation of CD8+ T cell memory. Science 297: 2060–2063.
    Campbell DJ, Kim CH and Butcher EC (2001) Separable effector T cell populations specialized for B cell help or tissue inflammation. Nature Immunology 2: 876–881.
    Chtanova T, Tangye SG, Newton R et al. (2004) T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-TH1/TH2 effector cells that provide help for B cells. Journal of Immunology 173: 68–78.
    Curtis MM and Way SS (2009) Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 126: 177–185.
    Dardalhon V, Awasthi A, Kwon H et al. (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3- effector T cells. Nature Immunology 9: 1347–1355.
    Doranz BJ, Berson JF, Rucker J et al. (1997) Chemokine receptors as fusion cofactors for human immunodeficiency virus type 1 (HIV-1). Immunological Research 16: 15–28.
    Faria AM and Weiner HL (2006) Oral tolerance: therapeutic implications for autoimmune diseases. Clinical Development of Immunology 13: 143–157.
    Fazilleau N, Mark L, McHeyzer-Williams LJ et al. (2009) Follicular helper T cells: lineage and location. Immunity 30: 324–335.
    Hwang ES, Szabo SJ, Schwartzberg PL et al. (2005) T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science 307: 430–433.
    Ivanov II, McKenzie BS, Zhou L et al. (2006) The orphan nuclear receptor RORt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126: 1121–1133.
    Kano S, Sato K, Morishita Y et al. (2008) The contribution of transcription factor IRF1 to the interferon-gamma-interleukin 12 signaling axis and TH1 versus TH-17 differentiation of CD4+ T cells. Nature Immunology 9: 34–41.
    Kim CH, Rott LS, Clark-Lewis I et al. (2001) Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. Journal of Experimental Medicine 193: 1373–1381.
    Korn T, Bettelli E, Gao W et al. (2007) IL-21 initiates an alternative pathway to induce proinflammatory TH-17 cells. Nature 448: 484–487.
    Kuchroo VK, Das MP, Brown JA et al. (1995) B7-1 and B7-2 costimulatory molecules activate differentially the TH1/TH2 developmental pathways: application to autoimmune disease therapy. Cell 80: 707–718.
    Li MO, Wan YY, Flavell RA et al. (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates TH1- and TH-17-cell differentiation. Immunity 26: 579–591.
    Lingnau K, Hoehn P, Kerdine S et al. (1998) IL-4 in combination with TGF- favors an alternative pathway of TH1 development independent of IL-12. Journal of Immunology 161: 4709–4718.
    Manel N, Unutmaz D and Littman DR (2008) The differentiation of human TH-17 cells requires transforming growth factor-beta and induction of the nuclear receptor RORt. Nature Immunology 9: 641–649.
    Mangan PR, Harrington LE, O'Quinn DB et al. (2006) Transforming growth factor-beta induces development of the TH-17 lineage. Nature 441: 231–234.
    Martin-Orozco N, Chung Y, Chang SH et al. (2009) TH-17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into TH1 cells. European Journal of Immunology 39: 216–224.
    Mucida D, Park Y, Kim G et al. (2007) Reciprocal TH-17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256–260.
    Nagata K, Tanaka K, Ogawa K et al. (1999) Selective expression of a novel surface molecule by human TH2 cells in vivo. Journal of Immunology 162: 1278–1286.
    Nurieva R, Yang XO, Martinez G et al. (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448: 480–483.
    Nurieva RI, Chung Y, Hwang D et al. (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29: 138–149.
    Quintana FJ, Basso AS, Iglesias AH et al. (2008) Control of Treg and TH-17 cell differentiation by the aryl hydrocarbon receptor. Nature 453: 65–71.
    Rasheed AU, Rahn HP, Sallusto F et al. (2006) Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression. European Journal of Immunology 36: 1892–1903.
    Ridge JP, Di Rosa F and Matzinger P (1998) A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature 393: 474–478.
    Robinson D, Shibuya K, Mui A et al. (1997) IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFB. Immunity 7: 571–581.
    Roncarolo MG, Gregori S, Battaglia M et al. (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunological Review 212: 28–50.
    Schmitz J, Owyang A, Oldham E et al. (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23: 479–490.
    Schoenberger SP, Toes RE, van der Vroot EI et al. (1998) T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 393: 480–483.
    Smith CM, Wilson NS, Waithman J et al. (2004) Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nature Immunology 5: 1143–1148.
    Sun JC, Williams MA and Bevan MJ (2004) CD4+ T cells are required for the maintenance, not programming, of memory CD8+ T cells after acute infection. Nature Immunology 5: 927–933.
    Suto A, Wurster AL, Reiner SL et al. (2006) IL-21 inhibits IFN- production in developing TH1 cells through the repression of Eomesodermin expression. Journal of Immunology 177: 3721–3727.
    Szabo SJ, Kim ST, Costa GL et al. (2000) A novel transcription factor, T-bet, directs TH1 lineage commitment. Cell 100: 655–669.
    Veldhoen M, Hirota K, Westendorf AM et al. (2008) The aryl hydrocarbon receptor links TH-17-cell-mediated autoimmunity to environmental toxins. Nature 453: 106–109.
    Veldhoen M, Hocking RJ, Atkins CJ et al. (2006) TGF in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24: 179–189.
    Vergelli M, Le H, van Noort JM et al. (1996) A novel population of CD4+CD56+ myelin-reactive T cells lyses target cells expressing CD56/neural cell adhesion molecule. Journal of Immunology 157: 679–688.
    Volpe E, Servant N, Zollinger R et al. (2008) A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nature Immunology 9: 650–657.
    Wilson NJ, Boniface K, Chan JR et al. (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunology 8: 950–957.
    Yang J, Zhu H, Murphy TL et al. (2001) IL-18stimulated GADD45 beta required in cytokine-induced, but not TCR-induced, IFN- production. Nature Immunology 2: 157–164.
    Yang L, Anderson DE, Baecher-Allan C et al. (2008) IL-21 and TGF- are required for differentiation of human TH-17 cells. Nature 454: 350–352.
    Zhang F, Meng G and Strober W (2008) Interactions among the transcription factors Runx1, RORt and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nature Immunology 9: 1297–1306.
    Zhou L, Ivanov II, Spolski R et al. (2007) IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nature Immunology 8: 967–974.
    Zhou L, Lopes JE, Chong MM et al. (2008) TGF--induced Foxp3 inhibits TH-17 cell differentiation by antagonizing RORt function. Nature 453: 236–240.
    Zhu J, Min B, Hu-Li J et al. (2004) Conditional deletion of Gata3 shows its essential function in TH1TH2 responses. Nature Immunology 5: 1157–1165.
 Further Reading
    Awasthi A, Murugaiyan G and Kuchroo VK (2008) Interplay between effector TH-17 and regulatory T cells. Journal of Clinical Immunology 28: 660–670.
    Gately MK, Renzetti LM, Magram J et al. (1998) The interleukin-12/interleukin-12-receptor system: role in normal and pathologic immune responses. Annual Review of Immunology 16: 495–521.
    King C, Tangye SG and Mackay CR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annual Review of Immunology 26: 741–766.
    Korn T, Bettelli E, Oukka M et al. (2009) IL-17 and TH-17 cells. Annual Review of Immunology 27: 485–517.
    Sallusto F, Lanzavecchia A and Mackay CR (1998) Chemokines and chemokine receptors in T-cell priming and TH1/TH2-mediated responses. Immunology Today 19: 568–574.
    Sinigaglia F, D'Ambrosio D, Panina-Bordignon P et al. (1999) Regulation of the IL-12/IL-12R axis: a critical step in T-helper cell differentiation and effector function. Immunological Review 170: 65–72.

Related Sub-Topics:

Cells of the Immune System
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: T Lymphocytes: Helpers
 
How to Cite close
Kawachi, Izumi, and Kondo, Takayuki(Dec 2009) T Lymphocytes: Helpers. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001224.pub2]