Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The functional plasticity of T cell subsets


In 1986, Robert Coffman and Timothy Mossman first described the division of CD4+ T cells into functional subsets, termed T helper 1 (TH1) and TH2, based on cytokine production, and in doing so unwittingly opened a Pandora's box of complexity and controversy. Although the mechanisms that regulate TH1 and TH2 cells are now well known, recent descriptions of other CD4+ T cell subsets — such as regulatory T cells, T follicular helper cells, TH17, TH22 and most recently TH9 and TH22 cells — have questioned how we think of T cell subsets and what commitment to a functional T cell subset means. Here, Nature Reviews Immunology asks four leaders in the field their thoughts on the functional plasticity of T cell subsets.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. Bending, D. et al. Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J. Clin. Invest. 119, 565–572 (2009).

    CAS  Article  Google Scholar 

  2. Lee, Y. K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Veldhoen, M. et al. Transforming growth factor-β 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nature Immunol. 9, 1341–1346 (2008).

    CAS  Article  Google Scholar 

  4. Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl Acad. Sci. USA 106, 1903–1908 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. Zhou, X., Bailey-Bucktrout, S., Jeker, L. T. & Bluestone, J. A. Plasticity of CD4+ FoxP3+ T cells. Curr. Opin. Immunol. 21, 281–285 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nature Immunol. 10, 1000–1007 (2009).

    CAS  Article  Google Scholar 

  7. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

    CAS  Article  PubMed  Google Scholar 

  8. Nurieva, R. I. et al. 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 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Zaretsky, A. G. et al. T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J. Exp. Med. 206, 991–999 (2009).

    CAS  Article  PubMed Central  Google Scholar 

  10. King, I. L. & Mohrs, M. IL-4-producing CD4+ T cells in reactive lymph nodes during helminth infection are T follicular helper cells. J. Exp. Med. 206, 1001–1007 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. Reinhardt, R. L., Liang, H. E. & Locksley, R. M. Cytokine-secreting follicular T cells shape the antibody repertoire. Nature Immunol. 10, 385–393 (2009).

    CAS  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  13. Lee, Y. K., Mukasa, R., Hatton, R. D. & Weaver, C. T. Developmental plasticity of Th17 and Treg cells. Curr. Opin. Immunol. 21, 274–280 (2009).

    CAS  Article  PubMed  Google Scholar 

  14. Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646–655 (2009).

    CAS  Article  PubMed  Google Scholar 

  15. Xu, L., Kitani, A., Fuss, I. & Strober, W. Cutting edge: regulatory T cells induce CD4+CD25Foxp3 T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J. Immunol. 178, 6725–6729 (2007).

    CAS  Article  PubMed  Google Scholar 

  16. Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nature Immunol. 10, 595–602 (2009).

    CAS  Article  Google Scholar 

  17. Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Shi, G. et al. Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J. Immunol. 181, 7205–7213 (2008).

    CAS  Article  PubMed  Google Scholar 

  19. Duhen, T. et al. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nature Immunol. 10, 857–863 (2009).

    CAS  Article  Google Scholar 

  20. Trifari, S. et al. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nature Immunol. 10, 864–871 (2009).

    CAS  Article  Google Scholar 

  21. Bernstein, B. E., Meissner, A. & Lander, E. S. The mammalian epigenome. Cell 128, 669–681 (2007).

    CAS  Article  PubMed  Google Scholar 

  22. Ng, R. K. & Gurdon, J. B. Epigenetic inheritance of cell differentiation status. Cell Cycle 7, 1173–1177 (2008).

    CAS  Article  PubMed  Google Scholar 

  23. Rieger, M. A. et al. Haematopoietic cytokines can instruct lineage choice. Science 325, 217–218 (2009).

    CAS  Article  PubMed  Google Scholar 

  24. Zhou, X. et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 1983–1991 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127–137 (2008).

    CAS  Article  PubMed  Google Scholar 

  26. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

    CAS  Article  PubMed  Google Scholar 

  27. Yang, X. O. et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29, 44–56 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. Burchill, M. A. et al. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280–290 (2007).

    CAS  Article  PubMed  Google Scholar 

  29. Wei, L., Laurence, A. & O'Shea, J. J. New insights into the roles of Stat5a/b and Stat3 in T cell development and differentiation. Semin. Cell Dev. Biol. 19, 394–400 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Gett, A. V., Sallusto, F., Lanzavecchia, A. & Geginat, J. T cell fitness determined by signal strength. Nature Immunol. 4, 355–360 (2003).

    CAS  Article  Google Scholar 

  33. Sumen, C., Mempel, T. R., Mazo, I. B. & von Andrian, U. H. Intravital microscopy: visualizing immunity in context. Immunity 21, 315–329 (2004).

    CAS  PubMed  Google Scholar 

  34. Reiner, S. L. Decision making during the conception and career of CD4+ T cells. Nature Rev. Immunol. 9, 81–82 (2009).

    CAS  Article  Google Scholar 

  35. Locksley, R. M. Nine lives: plasticity among T helper cell subsets. J. Exp. Med. 206, 1643–1646 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. McGeachy, M. J. et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nature Immunol. 10, 314–324 (2009).

    CAS  Article  Google Scholar 

  37. Veldhoen, M. et al. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  Article  PubMed  Google Scholar 

  38. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    CAS  Article  PubMed  Google Scholar 

  39. Veldhoen, M. et al. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med. 206, 43–49 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Takemoto, N. et al. Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J. Immunol. 177, 7515–7519 (2006).

    CAS  Article  PubMed  Google Scholar 

  41. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper lineage commitment. Immunity 22 Jul 2009 (doi:10.1016/j.immuni.2009.07.002).

    CAS  Article  PubMed  Google Scholar 

  42. Kusam, S., Toney, L. M., Sato, H. & Dent, A. L. Inhibition of Th2 differentiation and GATA-3 expression by BCL-6. J. Immunol. 170, 2435–2441 (2003).

    CAS  Article  PubMed  Google Scholar 

  43. Curotto de Lafaille, M. A. & Lafaille, J. J. Natural and adaptive Foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30, 626–635 (2009).

    CAS  Article  PubMed  Google Scholar 

  44. Yamanaka, S. Pluripotency and nuclear reprogramming. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 2079–2087 (2008).

    CAS  Article  Google Scholar 

  45. Gurdon, J. B. & Melton, D. A. Nuclear reprogramming in cells. Science 322, 1811–1815 (2008).

    CAS  Article  PubMed  Google Scholar 

  46. Zhou, Q. & Melton, D. A. Extreme makeover: converting one cell into another. Cell Stem Cell 3, 382–388 (2008).

    CAS  Article  PubMed  Google Scholar 

  47. Johnson, L. D. & Jameson, S. C. Immunology. A chronic need for IL-21. Science 324, 1525–1526 (2009).

    CAS  Article  PubMed  Google Scholar 

  48. Lexberg, M. H. et al. Th memory for interleukin-17 expression is stable in vivo. Eur. J. Immunol. 38, 2654–2664 (2008).

    CAS  Article  PubMed  Google Scholar 

  49. Annunziato, F. et al. Phenotypic and functional features of human Th17 cells. J. Exp. Med. 204, 1849–1861 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references


J.B. would like to thank S. Bailey-Bucktrout, L. Jeker and X. Zhou for their hard work and thoughtful comments, M. Anderson, R. Locksley and A. Abbas for critical reading of this piece and the US National Institute of Health, Juvenile Diabetes Research Foundation, and University of California, San Francisco Diabetes Center for financial support.

C.R.M.'s views in this article are derived from work and discussions with D. Yu, C. Vinuesa and C. King. Charles Mackay is supported by the National Health and Medical Research Council of Australia.

J.J.O'S. would like to thank A. Laurence, L. Wei, V. Sartorelli, M. Gadina, R. Siegel and Y.e Belkaid for their lively discussion of this issue; however, I also wish to apologize to the members of my laboratory for taking so much time in lab meetings and journal clubs for endlessly debating this topic.

Author information

Authors and Affiliations


Related links

Related links


Jeffery A. Bluestone's homepage

John J. O'shea's homepage

Brigitta stockinger's homepage

CD4+ T cell diversity


γδ T cells

T cells that express the γδ T cell receptor. These T cells are present in the skin, vagina and intestinal epithelium as intraepithelial lymphocytes. Although the exact function of these T cells is unknown, it has been suggested that mucosal γδ T cells are involved in innate immune responses.

Asymmetrical cell division

A type of division that produces two daughter cells with different properties. This is in contrast to normal cell division, which give rise to equivalent daughter cells. Notably, stem cells can divide asymmetrically to give rise to two distinct daughter cells: one copy of themselves and one cell programmed to differentiate into another cell type.

Class switching

The switch from expressing IgM to expressing other isotypes such as IgG, IgA or IgE that some B cells make after recognizing their cognate antigen. The decision of which isotype is generated is strongly influenced by the specific cytokine milieu and other cells such as T helper cells.

Germinal centre

A highly specialized and dynamic microenvironment that gives rise to secondary B cell follicles during an immune response. It is the main site of B cell maturation, leading to the generation of memory B cells and plasma cells, which produce high-affinity antibody.

Lymphoid-tissue inducer cell

A cell that is present in developing lymph nodes, Peyer's patches and nasopharynx-associated lymphoid tissue (NALT) and is required for the development of these lymphoid organs.

Lymphopenic mice

Mice that have lost both B and T cells, for example severe combined immunodeficiency mice or recombination activation gene-deficient mice, which lack an enzyme required for the generation of T and B cell receptors, or a loss of T cells only, as seen in nu/nu mice, which lack a thymus. T cell lymphopenia can be induced in mice by thymectomy on day three of life.


Small RNA molecules that regulate the expression of genes by binding to the 3′-untranslated regions of specific mRNAs.

Non-obese diabetic (NOD) mice

NOD mice spontaneously develop type 1 diabetes mellitus as a result of autoreactive T cell-mediated destruction of pancreatic β-islet cells.

Peyer's patches

Collections of lymphoid tissue located in the mucosa of the small intestine, with an outer epithelium layer consisting of specialized epithelial cells called M cells.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, particularly in the kidney. Patients with SLE generally have abnormal B and T cell function.

T follicular helper (TFH) cell

A CD4+ T cell that provides help to B cells in follicles and germinal centres. The TFH cell signature includes the expression of CXCR5, ICOS, CD40 ligand and IL-21, factors that mediate TFH cell homing to follicles and B cell help.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Bluestone, J., Mackay, C., O'Shea, J. et al. The functional plasticity of T cell subsets. Nat Rev Immunol 9, 811–816 (2009).

Download citation

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing