T Lymphocytes: Helpers

Abstract

Helper T lymphocytes (TH) are major histocompatibility complex (MHC) class II restricted CD4+ T cells that can be divided into several subsets depending on their cytokine releasing patterns: T‐helper 1 (TH1), TH2, TH17, T‐follicular helper (TFH), forkhead box P3+ regulatory T (Treg) cells and the recently described TH9 and TH22 cells and others. TH1 cells activate infected macrophages for the destruction of intracellular pathogens. TH2 and TFH cells provide help to B cells for antibody production. TH17 cells enhance neutrophil response for extracellular pathogens. Treg cells actively suppress immune reactions and help prevent the development of autoimmunity during immune response. It was initially thought that each TH subset retained a stable phenotype with a distinct lineage and played a distinct role in host defense and autoimmunity. Considerable overlap and flexibility of cytokine production by CD4+ T cells is challenging earlier concepts.

Key Concepts:

  • Helper T lymphocytes (TH) are MHC class II restricted CD4+ T cells that can be divided into several subsets of cytokine releasing patterns: T‐helper 1 (TH1), T‐helper 2 (TH2), T‐helper 17 (TH17), regulatory T (Treg), T‐follicular helper (TFH) and others.

  • TH cell subsets express a distinct set of genes that encode hallmark cytokines and unique transcription factors.

  • IFN‐γ, IL‐4, IL‐17, IL‐10/TGF‐β and IL‐21 are the representative cytokines of TH1, TH2, TH17, Treg and TFH 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 defense against intracellular organisms.

  • TH2 cells enhance antibody production by B cells.

  • TH17 cells are potent inducers of tissue inflammation in autoimmune diseases and confer protection against extracellular bacterial and fungal pathogens.

  • Treg cells consist of a heterogeneous class of cells that suppress T‐cell activity and help prevent the development of autoimmunity during immune response.

  • 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.

The classical view of TH cell differentiation. 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 (TH17), regulatory T (Treg), and follicular helper T (TFH) effector cells that can migrate to appropriate tissues. Master regulators and STAT family members collaborate in T cell differentiation and expansion: T‐bet and STAT4 for TH1, GATA3 and STAT5 for TH2, RORγt and STAT3 for TH17, forkhead box P3 (Foxp3) and STAT5 for iTreg, and Bcl6 and STAT3 for TFH. Other transcription factors are either secondary to master regulators and STAT proteins or responsible for the induction of master regulators. Polarised T cells produce different sets of cytokines, and TH1, TH2, TH17, Treg and TFH cells cross‐regulate each other by the cytokines they produce. TH1 cells produce cytokines that activate macrophages, enabling them to destroy intracellular microorganisms more efficiently. TH2 cells produce cytokines that recruit and activate eosinophils, mast cells and basophils and promote barrier immunity at mucosal surfaces. TH17 cells produce IL‐17 family cytokines that induce local epithelial cells to secret chemokines that recruit neutrophils to sites of infection. TFH cells, a subset localised in B cell follicles, produce IFN‐γ that activates B cells to produce strongly opsonising antibodies that belong to certain IgG subclasses. TFH cells also produce IL‐4, driving B cells to differentiate and produce immunoglobulins of other types, especially IgE. Treg cells are a heterogeneous class of cells that suppress T cell activity and help prevent the development of autoimmunity during immune responses. APC, antigen‐presenting cell; CTLA‐4, cytotoxic T–lymphocyte antigen 4; ICOS, inducible T‐cell co‐stimulator; IFN‐γ, interferon‐γ; IL, interleukin; and TGF‐β, transforming growth factor β.

Figure 2.

Diversity and plasticity of TH Cells. Recent studies of TH cells have revealed flexibility in cytokine production, and there are now many examples of plasticity of the TH phenotype. CD4+ T cells can shift their profile of cytokine production and can express more than one master regulator. This schema may support the idea that elements of both terminal differentiation in the case of cytokine genes and plasticity in the case of master regulators genes can coexist within the same TH cell subset. Understanding how to control the stability and plasticity of TH cells will have important therapeutic applications for infection and autoimmunity.

Figure 3. T–B interaction: T cell help to B cells. (a) TH cells recognise processed antigen peptides and are activated. The specific interaction of an antigen‐binding B cell with an armed TH cell leads to the expression of the B cell stimulatory molecule CD40 ligand on the TH cell surface and to the secretion of B cell stimulatory cytokines IL‐4, IL‐5, IL‐6, or IL‐21 that drive the proliferation and differentiation of the B cells 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 event leads to expression of CD40L on T cells, after which CD40/CD40L interaction causes upregulation of B7 co‐stimulatory 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 co‐stimulatory 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 and differentiation of the B cells into antibody‐secreting plasma cells.
Figure 4.

Activation of macrophages. Helper T cells produce macrophage‐activating factors such as IFN‐γ and upregulate CD40 ligand (CD40L), followed by recognition of bacterial peptides‐MHC class II on infected macrophages. GM–CSF, granulocyte‐macrophage colony‐stimulating factor; IFN‐γ, interferon‐γ; and TNF‐α, tumor necrosis factor‐α.

Figure 5.

Models of helper functions 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 Th17 cells. Journal of Experimental Medicine 204: 1849–1861.

Bevan MJ (2004) Helping the CD8(+) T‐cell response. Nature Reviews Immunology 4: 595–602.

Crotty S, Johnston RJ and Schoenberger SP (2010) Effector and Monories: Bcl‐6 and Blimp‐1 in T and B lymphocyte differentiation. Nature Immunology 11: 114–120.

Curtis MM and Way SS (2009) Interleukin‐17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology 126: 177–185.

Dominguez‐Villar M, Baecher‐Allan CM and Hafler DA (2011) Identification of T helper type 1‐like, Foxp3+ regulatory T cells in human autoimmune disease. Nature Medicine 17: 673–675.

Duhen T, Geiger R, Jarrossay D, Lanzavecchia A and Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin‐homing memory T cells. Nature Immunology 10: 857–863.

Faria AM and Weiner HL (2006) Oral tolerance: therapeutic implications for autoimmune diseases. Clinical and Developmental Immunology 13: 143–157.

Fazilleau N, Mark L, McHeyzer-Williams LJ and McHeyzer-Williams MG (2009) Follicular helper T cells: lineage and location. Immunity 30: 324–335.

Feau S, Garcia Z, Arens R et al. (2012) The CD4+ T‐cell help signal is transmitter from APC to CD8+ T‐cells via CD27‐CD70 interactions. Nature Communications 3: 948. 10.1038/ncomms 1948.

Furuta S, Kagami S, Tamachi T et al. (2008) Overlapping and distinct roles of STAT4 and T‐bet in the regulation of T cell differentiation and allergic airway inflammation. Journal of Immunology 180: 6656–6662.

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: 967–971.

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: 116–128.

Hill JA, Feuerer M, Tash K et al. (2007) Foxp3 transcription‐factor‐dependent and ‐independent regulation of the regulatory T cell transcriptional signature. Immunity 27: 786–800.

Hwang ES, Szabo SJ, Schwartzberg PL and Glimcher LH (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 RORgammat directs the differentiation program of proinflammatory IL‐17+ T helper cells. Cell 126: 1121–1133.

Josefowicz SZ, Lu LF and Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annual Review of Immunology 30: 531–564.

Kanno Y, Vahedi G, Hirahara K, Singleton K and O'Shea JJ (2012) Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annual Review of Immunology 30: 707–731.

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.

Li MO, Wan YY and Flavell RA (2007) T cell‐produced transforming growth factor‐beta1 controls T cell tolerance and regulates Th1‐ and Th17‐cell differentiation. Immunity 26: 579–591.

Maddur MS, Miossec P, Kaveri SV and Bayry J (2012) The Th17 cells: Biology, Pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategiess. American Journal of Pathology 39: 216–224.

Martin-Orozco N, Chung Y, Chang SH, Wang YH and Dong C (2009) Th17 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 TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256–260.

Mukasa R, Balasubramani A, Lee YK et al. (2010) Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper cell lineage. Immunity 32: 616–627.

Murphy KM and Stockinger B (2010) Effector T cell plasticity: flexibility in the face of changing circumstances. Nature Immunology 11: 674–680.

Nakayamada S, Kanno Y, Takahashi H et al. (2011) Early Th1 cell differentiation is marked by a Tfh cell‐like transition. Immunity 35: 919–931.

Nakayamada S, Takahashi H, Kanno Y and O'Shea JJ (2012) Helper T cell diversity and plasticity. Current Opinion in Immunology 24: 297–302.

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.

O'Shea JJ and Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327: 1098–1102.

Quintana FJ, Basso AS, Iglesias AH et al. (2008) Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor. Nature 453: 65–71.

Roncarolo MG, Gregori S, Battaglia M et al. (2006) Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans. Immunological Reviews 212: 28–50.

Saraiva M and O'Garra A (2010) The regulation of IL‐10 production by immune cells. Nature Reviews Immunology 10: 170–181.

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.

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 and Grusby MJ (2006) IL‐21 inhibits IFN‐gamma 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.

Trifari S, Kaplan CD, Tran EH, Crellin NK and Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)‐17, T(H)1 and T(H)2 cells. Nature Immunology 10: 864–871.

Tsuji M, Komatsu N, Kawamoto S et al. (2009) Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323: 1488–1492.

Veldhoen M, Hirota K, Westendorf AM et al. (2008) The aryl hydrocarbon receptor links TH17‐cell‐mediated autoimmunity to environmental toxins. Nature 453: 106–109.

Veldhoen M, Uyttenhove C, van Snick J et al. (2008) Transforming growth factor‐beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9‐producing subset. Nature Immunology 9: 1341–1346.

Voo KS, Wang YH, Santori FR et al. (2009) Identification of IL‐17‐producing FOXP3+ regulatory T cells in humans. Proceedings of the National Academy of Sciences of the USA 106: 4793–4798.

Yang J, Zhu H, Murphy TL, Ouyang W and Murphy KM (2001) IL‐18‐stimulated GADD45 beta required in cytokine‐induced, but not TCR‐induced, IFN‐gamma production. Nature Immunology 2: 157–164.

Yu D, Batten M, Mackay CR and King C (2009) Lineage specification and heterogeneity of T follicular helper cells. Current Opinion in Immunology 21: 619–625.

Zhang F, Meng G and Strober W (2008) Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17‐producing T cells. Nature Immunology 9: 1297–1306.

Zhou L, Lopes JE, Chong MM et al. (2008) TGF‐beta‐induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453: 236–240.

Zhou VW, Goren A and Bernstein BE (2011) Charting histone modifications and the functional organization of mammalian genomes. Nature Reviews Genetics 12: 7–12.

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. Nature Immunology 5: 1157–1165.

Zhu J, Yamane H and Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annual Review of Immunology 28: 445–489.

Further Reading

Awasthi A, Murugaiyan G and Kuchroo VK (2008) Interplay between effector Th17 and regulatory T cells. Journal of Clinical Immunology 28: 660–670.

Bevan MJ (2004) Helping the CD8(+) T‐cell response. Nature Reviews Immunology 4: 595–602.

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.

Josefowicz SZ, Lu LF and Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annual Review of Immunology 30: 531–564.

King C and Sprent J (2012) Emerging cellular networks for regulation of T follicular helper cells. Trends in Immunology 33: 59–65.

O'Shea JJ and Paul WE (2010) Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327: 1098–1102.

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.

Yamane H and Paul WE (2012) Cytokines of the gamma(c) family control CD4+ T cell differentiation and function. Nature Immunology 13: 1037–1044.

Zhu J, Yamane H and Paul WE (2010) Differentiation of effector CD4 T cell populations (*). Annual Review of Immunology 28: 445–489.

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

* Required Field

How to Cite close
Kawachi, Izumi, and Kondo, Takayuki(Sep 2013) T Lymphocytes: Helpers. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001224.pub3]