T Lymphocytes: Plasticity of Subsets


The initial characterisation of both mouse and human T cells described distinct and sharply defined cytokine patterns that were relatively stable and were functionally specialised for successfully attacking different pathogens. Additional phenotypes were then described, extending the range of functional types. However, more recently there have been many reports of further changes in cytokine patterns, and it is clear that all the recognised phenotypes were more plastic than originally thought. In particular, many intermediates between established subsets have been reported, for example Th1/Th17 cells expressing both IFNγ (interferon‐gamma) and IL (interleukin)‐17. This plasticity provides extra versatility for the immune system to adapt to changing infections and to altered requirements in different locations. A model of stochastic differentiation is presented, to visualise potential differentiation modes in the framework of a landscape model and to try to encourage discussion and experimentation regarding different mechanisms for plasticity.

Key Concepts

  • Initial models of highly stable T‐cell subsets were useful but underestimated diversity.
  • Flexibility is overlaid on partial stability.
  • Many intermediate phenotypes can be induced.
  • Several questions remain regarding temporary versus long‐term plasticity alterations.
  • Models for visualising differentiation need to be modified to include flexibility around a theme.
  • Incorporation of stochastic trends may give a more useful representation of differentiation.

Keywords: T‐cell subset; stochastic variation; stability; plasticity; effector adaptation; intermediate T‐cell phenotypes

Figure 1. Plasticity of major recognised Th effector phenotypes. Transitions between different Th phenotypes are shown, concentrating on states leading to or deriving from Th1, Th2 and Th17 cells. Only transitions validated by experimental evidence are shown – the numbers in black circles indicate the reference number supporting each transition. Tfh and Th22 cells have been omitted from the diagram. The focus of the diagram is on transitions from the canonical phenotypes, (Th1, Th2, etc.) to intermediate forms, such as Th1/Th17. Although there is some evidence for complete conversion, for example Th1 to Th2, these experiments are normally less conclusive because T cells do not synthesise their entire cytokine repertoire in response to each stimulation. Numbers next to each transition in the figure refer to the following references: Sad and Mosmann , Sallusto et al. , Divekar et al. , Panzer et al. , Hegazy et al. , Wang et al. , Xu et al. , Brown et al. , Annunziato et al. ; Lee et al. , Dardalhon et al. , Veldhoen et al. , Gagliani et al. .


Annunziato F, Cosmi L, Santarlasci V, et al. (2007) Phenotypic and functional features of human Th17 cells. Journal of Experimental Medicine 204 (8): 1849–1861.

Breitfeld D, Ohl L, Kremmer E, et al. (2000) Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. Journal of Experimental Medicine 192 (11): 1545–1552.

Brown CC, Esterhazy D, Sarde A, et al. (2015) Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 42 (3): 499–511.

Buchholz VR, Flossdorf M, Hensel I, et al. (2013) Disparate individual fates compose robust CD8+ T cell immunity. Science 340 (6132): 630–635.

Bucy RP, Panoskaltsis‐Mortari A, Huang GQ, et al. (1994) Heterogeneity of single cell cytokine gene expression in clonal T cell populations. Journal of Experimental Medicine 180 (4): 1251–1262.

Cantor H and Boyse EA (1975) Functional subclasses of T‐lymphocytes bearing different Ly antigens. I. The generation of functionally distinct T‐cell subclasses is a differentiative process independent of antigen. Journal of Experimental Medicine 141 (6): 1376–1389.

Chang HC, Sehra S, Goswami R, et al. (2010) The transcription factor PU.1 is required for the development of IL‐9‐producing T cells and allergic inflammation. Nature Immunology 11 (6): 527–534.

Cherwinski HM, Schumacher JH, Brown KD, et al. (1987) Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. Journal of Experimental Medicine 166 (5): 1229–1244.

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

Crotty S (2012) The 1‐1‐1 fallacy. Immunological Reviews 247 (1): 133–142.

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 (12): 1347–1355.

Del Prete GF, De Carli M, Mastromauro C, et al. (1991) Purified protein derivative of Mycobacterium tuberculosis and excretory‐secretory antigen(s) of Toxocara canis expand in vitro human T cells with stable and opposite (type 1 T helper or type 2 T helper) profile of cytokine production. Journal of Clinical Investigation 88 (1): 346–350.

Divekar AA, Zaiss DM, Lee FE, et al. (2006) Protein vaccines induce uncommitted IL‐2‐secreting human and mouse CD4 T cells, whereas infections induce more IFN‐gamma‐secreting cells. Journal of Immunology 176 (3): 1465–1473.

Duhen T, Geiger R, Jarrossay D, et al. (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin‐homing memory T cells. Nature Immunology 10 (8): 857–863.

Else KJ and Grencis RK (1991) Cellular immune responses to the murine nematode parasite Trichuris muris. I. Differential cytokine production during acute or chronic infection. Immunology 72 (4): 508–513.

Fazilleau N, Mark L, McHeyzer‐Williams LJ, et al. (2009) Follicular helper T cells: lineage and location. Immunity 30 (3): 324–335.

Firestein GS, Roeder WD, Laxer JA, et al. (1989) A new murine CD4+ T cell subset with an unrestricted cytokine profile. Journal of Immunology 143 (2): 518–525.

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

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.

Hawkins ED, Turner ML, Dowling MR, et al. (2007) A model of immune regulation as a consequence of randomized lymphocyte division and death times. Proceedings of the National Academy of Sciences of the United States of America 104 (12): 5032–5037.

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.

Heinzel FP, Sadick MD, Holaday BJ, et al. (1989) Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. Journal of Experimental Medicine 169 (1): 59–72.

Huang W, Na L, Fidel PL, et al. (2004) Requirement of interleukin‐17A for systemic anti‐Candida albicans host defense in mice. Journal of Infectious Diseases 190 (3): 624–631.

Katzman SD and Fowell DJ (2008) Pathogen‐imposed skewing of mouse chemokine and cytokine expression at the infected tissue site. Journal of Clinical Investigation 118 (2): 801–811.

Kim J, Woods A, Becker‐Dunn E, et al. (1985) Distinct functional phenotypes of cloned Ia‐restricted helper T cells. Journal of Experimental Medicine 162 (1): 188–201.

Langrish CL, Chen Y, Blumenschein WM, et al. (2005) IL‐23 drives a pathogenic T cell population that induces autoimmune inflammation. Journal of Experimental Medicine 201 (2): 233–240.

Lee YK, Turner H, Maynard CL, et al. (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30 (1): 92–107.

Licona‐Limon P, Henao‐Mejia J, Temann AU, et al. (2013) Th9 cells drive host immunity against gastrointestinal worm infection. Immunity 39 (4): 744–757.

Lin L, Ibrahim AS, Xu X, et al. (2009) Th1‐Th17 cells mediate protective adaptive immunity against Staphylococcus aureus and Candida albicans infection in mice. PLoS Pathogens 5 (12): e1000703.

Maggi E, Del Prete G, Macchia D, et al. (1988) Profiles of lymphokine activities and helper function for IgE in human T cell clones. European Journal of Immunology 18 (7): 1045–1050.

Marrack P and Kappler JW (1976) Antigen‐specific and nonspecific mediatiors of T cell/B cell cooperation. II. Two helper T cells distinguished by their antigen sensitivities. Journal of Immunology 116 (5): 1373–1378.

Miller JF and Mitchell GF (1968) Cell to cell interaction in the immune response. I. Hemolysin‐forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes. Journal of Experimental Medicine 128 (4): 801–820.

Mosmann TR, Cherwinski H, Bond MW, et al. (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. Journal of Immunology 136 (7): 2348–2357.

Omenetti S and Pizarro TT (2015) The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Frontiers in Immunology 6: 639.

Osorio F, LeibundGut‐Landmann S, Lochner M, et al. (2008) DC activated via dectin‐1 convert Treg into IL‐17 producers. European Journal of Immunology 38 (12): 3274–3281.

Paliard X, de Waal MR, Yssel H, et al. (1988) Simultaneous production of IL‐2, IL‐4, and IFN‐gamma by activated human CD4+ and CD8+ T cell clones. Journal of Immunology 141 (3): 849–855.

Panzer M, Sitte S, Wirth S, et al. (2012) Rapid in vivo conversion of effector T cells into Th2 cells during helminth infection. Journal of Immunology 188 (2): 615–623.

Parish CR and Liew FY (1972) Immune response to chemically modified flagellin. 3. Enhanced cell‐mediated immunity during high and low zone antibody tolerance to flagellin. Journal of Experimental Medicine 135 (2): 298–311.

Rebhahn JA, Deng N, Sharma G, et al. (2014) An animated landscape representation of CD4 T‐cell differentiation, variability and plasticity: Insights into the behavior of populations versus cells. European Journal of Immunology 44 (8): 2216–2229. DOI: 10.1002/eji.201444645.

Sad S and Mosmann TR (1994) Single IL‐2‐secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. Journal of Immunology 153 (8): 3514–3522.

Sakaguchi S, Vignali DA, Rudensky AY, et al. (2013) The plasticity and stability of regulatory T cells. Nature Reviews. Immunology 13 (6): 461–467.

Sallusto F, Lenig D, Forster R, et al. (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401 (6754): 708–712.

Schaerli P, Willimann K, Lang AB, et al. (2000) CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. Journal of Experimental Medicine 192 (11): 1553–1562.

Scott P, Natovitz P, Coffman RL, et al. (1988) Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. Journal of Experimental Medicine 168 (5): 1675–1684.

Shih HY, Sciume G, Poholek AC, et al. (2014) Transcriptional and epigenetic networks of helper T and innate lymphoid cells. Immunological Reviews 261 (1): 23–49.

Suzuki Y, Orellana MA, Schreiber RD, et al. (1988) Interferon‐gamma: the major mediator of resistance against Toxoplasma gondii. Science 240 (4851): 516–518.

Trifari S, Kaplan CD, Tran EH, et al. (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 (8): 864–871.

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 (12): 1341–1346.

Wang X and Mosmann T (2001) In vivo priming of CD4 T cells that produce interleukin (IL)‐2 but not IL‐4 or interferon (IFN)‐gamma, and can subsequently differentiate into IL‐4‐ or IFN‐gamma‐secreting cells. Journal of Experimental Medicine 194 (8): 1069–1080.

Wang YH, Voo KS, Liu B, et al. (2010) A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL‐17 cytokine and promote the exacerbation of chronic allergic asthma. Journal of Experimental Medicine 207 (11): 2479–2491.

Wierenga EA, Snoek M, de Groot C, et al. (1990) Evidence for compartmentalization of functional subsets of CD2+ T lymphocytes in atopic patients. Journal of Immunology 144 (12): 4651–4656.

Xu L, Kitani A, Fuss I, et al. (2007) Cutting edge: regulatory T cells induce CD4+ CD25‐Foxp3‐ T cells or are self‐induced to become Th17 cells in the absence of exogenous TGF‐beta. Journal of Immunology 178 (11): 6725–6729.

Zaretsky AG, Taylor JJ, King IL, et al. (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. Journal of Experimental Medicine 206 (5): 991–999.

Further Reading

Basu R, Hatton RD and Weaver CT (2013) The Th17 family: flexibility follows function. Immunological Reviews 252 (1): 89–103.

Bonelli M, Shih HY, Hirahara K, et al. (2014) Helper T cell plasticity: impact of extrinsic and intrinsic signals on transcriptomes and epigenomes. Current Topics in Microbiology and Immunology 381: 279–326.

Bouchery T, Kyle R, Ronchese F and Le Gros G (2014) The differentiation of CD4(+) T‐helper cell subsets in the context of helminth parasite infection. Frontiers in Immunology 5: 487.

Brucklacher‐Waldert V, Carr EJ, Linterman MA and Veldhoen M (2014) Cellular plasticity of CD4+ T cells in the intestine. Frontiers in Immunology 5: 488.

DuPage M and Bluestone JA (2016) Harnessing the plasticity of CD4(+) T cells to treat immune‐mediated disease. Nature Reviews. Immunology 16 (3): 149–163.

Geginat J, Paroni M, Maglie S, et al. (2014) Plasticity of human CD4 T cell subsets. Frontiers in Immunology 5: 630.

Lee Y and Kuchroo V (2015) Defining the functional states of Th17 cells. F1000Research 4 (F1000 Faculty Rev): 132.

Mahnke YD, Brodie TM, Sallusto F, Roederer M and Lugli E (2013) The who's who of T‐cell differentiation: human memory T‐cell subsets. European Journal of Immunology 43 (11): 2797–2809.

Perez‐Mazliah D and Langhorne J (2014) CD4 T‐cell subsets in malaria: TH1/TH2 revisited. Frontiers in Immunology 5: 671.

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Mosmann, Tim R, and Rebhahn, Jonathan A(Nov 2016) T Lymphocytes: Plasticity of Subsets. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026253]