Abstract
Lineage-committed effector CD4+ T cells are generated at the peak of the primary response and are followed by heterogeneous populations of central and effector memory cells. Here we review the evidence that T helper type 1 (TH1) effector cells survive the contraction phase of the primary response and become effector memory cells. We discuss the applicability of this idea to the TH2 cell, TH17 helper T cell, follicular helper T cell (TFH cell) and induced regulatory T cell lineages. We also discuss how central memory cells are formed, with an emphasis on the role of B cells in this process.
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References
Davis, M.M. T cell receptor gene diversity and selection. Annu. Rev. Biochem. 59, 475–496 (1990).
Jenkins, M.K. et al. In vivo activation of antigen-specific CD4 T cells. Annu. Rev. Immunol. 19, 23–45 (2001).
Swain, S.L., Weinberg, A.D. & English, M. CD4+ T cell subsets. Lymphokine secretion of memory cells and of effector cells that develop from precursors in vitro. J. Immunol. 144, 1788–1799 (1990).
Zhu, J., Yamane, H. & Paul, W.E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445–489 (2010).
Reinhardt, R.L., Khoruts, A., Merica, R., Zell, T. & Jenkins, M.K. Visualizing the generation of memory CD4 T cells in the whole body. Nature 410, 101–105 (2001).
Seder, R.A. & Ahmed, R. Similarities and differences in CD4+ and CD8+ effector and memory T cell generation. Nat. Immunol. 4, 835–842 (2003).
Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745–763 (2004).
Cyster, J.G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, 127–159 (2005).
Lohning, M. et al. Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J. Exp. Med. 205, 53–61 (2008).This study shows that in vitro –derived CD4+ effector cells can become memory cells.
Harrington, L.E., Janowski, K.M., Oliver, J.R., Zajac, A.J. & Weaver, C.T. Memory CD4 T cells emerge from effector T-cell progenitors. Nature 452, 356–360 (2008).This paper shows that T H 1 effector cells can become memory cells in vivo.
Sallusto, F., Lenig, D., Forster, R., Lipp, M. & Lanzavecchia, A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401, 708–712 (1999).This study defines effector and central memory cells.
Kearney, E.R., Pape, K.A., Loh, D.Y. & Jenkins, M.K. Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1, 327–339 (1994).
Pape, K.A. et al. Use of adoptive transfer of T-cell-antigen-receptor-transgenic T cell for the study of T-cell activation in vivo. Immunol. Rev. 156, 67–78 (1997).
Marzo, A.L. et al. Initial T cell frequency dictates memory CD8+ T cell lineage commitment. Nat. Immunol. 6, 793–799 (2005).
Foulds, K.E. & Shen, H. Clonal competition inhibits the proliferation and differentiation of adoptively transferred TCR transgenic CD4 T cells in response to infection. J. Immunol. 176, 3037–3043 (2006).
Badovinac, V.P., Haring, J.S. & Harty, J.T. Initial T cell receptor transgenic cell precursor frequency dictates critical aspects of the CD8+ T cell response to infection. Immunity 26, 827–841 (2007).
Blair, D.A. & Lefrancois, L. Increased competition for antigen during priming negatively impacts the generation of memory CD4 T cells. Proc. Natl. Acad. Sci. USA 104, 15045–15050 (2007).
Hataye, J., Moon, J.J., Khoruts, A., Reilly, C. & Jenkins, M.K. Naive and memory CD4+ T cell survival controlled by clonal abundance. Science 312, 114–116 (2006).
Moon, J.J. et al. Naive CD4+ T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude. Immunity 27, 203–213 (2007).
Pepper, M. et al. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells. Nat. Immunol. 11, 83–89 (2010).This was the first demonstration of population expansion, contraction and memory T cell formation by polyclonal pMHCII-specific CD4+ T cells induced by bacterial infection.
Stephens, R. & Langhorne, J. Effector memory TH1 CD4 T cells are maintained in a mouse model of chronic malaria. PLoS Pathog. 6, e1001208 (2010).
Colpitts, S.L., Dalton, N.M. & Scott, P. IL-7 receptor expression provides the potential for long-term survival of both CD62Lhigh central memory T cells and TH1 effector cells during Leishmania major infection. J. Immunol. 182, 5702–5711 (2009).
Surh, C.D., Boyman, O., Purton, J.F. & Sprent, J. Homeostasis of memory T cells. Immunol. Rev. 211, 154–163 (2006).
Homann, D., Teyton, L. & Oldstone, M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory. Nat. Med. 7, 913–919 (2001).This study provided first evidence that CD4+ memory T cells are less stable than are CD8+ memory T cells.
Lin, E. et al. Heterogeneity among viral antigen-specific CD4+ T cells and their de novo recruitment during persistent polyomavirus infection. J. Immunol. 185, 1692–1700 (2010).
Purton, J.F. et al. Antiviral CD4+ memory T cells are IL-15 dependent. J. Exp. Med. 204, 951–961 (2007).This study shows an IL-15-dependent mechanism of CD4+ memory T cell survival.
Turtle, C.J., Swanson, H.M., Fujii, N., Estey, E.H. & Riddell, S.R. A distinct subset of self-renewing human memory CD8+ T cells survives cytotoxic chemotherapy. Immunity 31, 834–844 (2009).
Stetson, D.B., Mohrs, M., Mallet-Designe, V., Teyton, L. & Locksley, R.M. Rapid expansion and IL-4 expression by Leishmania-specific naive helper T cells in vivo. Immunity 17, 191–200 (2002).
Mohrs, M., Shinkai, K., Mohrs, K. & Locksley, R.M. Analysis of type 2 immunity in vivo with a bicistronic IL-4 reporter. Immunity 15, 303–311 (2001).
Zaph, C. et al. Persistence and function of central and effector memory CD4+ T cells following infection with a gastrointestinal helminth. J. Immunol. 177, 511–518 (2006).
Hendriks, J., Xiao, Y. & Borst, J. CD27 promotes survival of activated T cells and complements CD28 in generation and establishment of the effector T cell pool. J. Exp. Med. 198, 1369–1380 (2003).
Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).
Shi, G. et al. Phenotype switching by inflammation-inducing polarized TH17 cells, but not by TH1 cells. J. Immunol. 181, 7205–7213 (2008).
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).
Martin-Orozco, N., Chung, Y., Chang, S.H., Wang, Y.H. & Dong, C.T. H17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into TH1 cells. Eur. J. Immunol. 39, 216–224 (2009).
Lee, Y.K. et al. Late developmental plasticity in the T helper 17 lineage. Immunity 30, 92–107 (2009).
Abromson-Leeman, S., Bronson, R.T. & Dorf, M.E. Encephalitogenic T cells that stably express both T-bet and RORγt consistently produce IFNγ but have a spectrum of IL-17 profiles. J. Neuroimmunol. 215, 10–24 (2009).
Acosta-Rodriguez, E.V. et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat. Immunol. 8, 639–646 (2007).
Annunziato, F. et al. Phenotypic and functional features of human TH17 cells. J. Exp. Med. 204, 1849–1861 (2007).
Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).
Lazarevic, V. et al. T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nat. Immunol. 12, 96–104 (2011).
Ertelt, J.M. et al. Selective priming and expansion of antigen-specific Foxp3- CD4+ T cells during Listeria monocytogenes infection. J. Immunol. 182, 3032–3038 (2009).
Koch, M.A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).
Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000–1007 (2009).
King, C., Tangye, S.G. & Mackay, C.R. T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu. Rev. Immunol. 26, 741–766 (2008).
Fazilleau, N., Mark, L., McHeyzer-Williams, L.J. & McHeyzer-Williams, M.G. Follicular helper T cells: lineage and location. Immunity 30, 324–335 (2009).
Johnston, R.J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).
Rasheed, A.U., Rahn, H.P., Sallusto, F., Lipp, M. & Muller, G. Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression. Eur. J. Immunol. 36, 1892–1903 (2006).
Morita, R. et al. Human blood CXCR5+CD4+ T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34, 108–121 (2011).
Breitfeld, D. et al. Follicular B helper T cells express CXC chemokine receptor 5, localize to B cell follicles, and support immunoglobulin production. J. Exp. Med. 192, 1545–1552 (2000).
Wang, X. & Mosmann, T. In vivo priming of CD4 T cells that produce interleukin (IL)-2 but not IL-4 or interferon (IFN)-γ, and can subsequently differentiate into IL-4- or IFN-γ-secreting cells. J. Exp. Med. 194, 1069–1080 (2001).
Catron, D.M., Rusch, L.K., Hataye, J., Itano, A.A. & Jenkins, M.K. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells. J. Exp. Med. 203, 1045–1054 (2006).
Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).
Pearce, E.L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).
Rutishauser, R.L. et al. Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity 31, 296–308 (2009).
Gudmundsdottir, H., Wells, A.D. & Turka, L.A. Dynamics and requirements of T cell clonal expansion in vivo at the single-cell level: effector function is linked to proliferative capacity. J. Immunol. 162, 5212–5223 (1999).
Caserta, S., Kleczkowska, J., Mondino, A. & Zamoyska, R. Reduced functional avidity promotes central and effector memory CD4 T cell responses to tumor-associated antigens. J. Immunol. 185, 6545–6554 (2010).
Whitmire, J.K. et al. Requirement of B cells for generating CD4+ T cell memory. J. Immunol. 182, 1868–1876 (2009).
Dong, C. et al. ICOS co-stimulatory receptor is essential for T-cell activation and function. Nature 409, 97–101 (2001).
McAdam, A.J. et al. Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells. J. Immunol. 165, 5035–5040 (2000).
Kadkhoda, K. et al. TH1 cytokine responses fail to effectively control Chlamydia lung infection in ICOS ligand knockout mice. J. Immunol. 184, 3780–3788 (2010).
Grimbacher, B. et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4, 261–268 (2003).
Bossaller, L. et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 177, 4927–4932 (2006).
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).
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We thank A. Pagán and J. Taylor for discussions.
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Pepper, M., Jenkins, M. Origins of CD4+ effector and central memory T cells. Nat Immunol 12, 467–471 (2011). https://doi.org/10.1038/ni.2038
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DOI: https://doi.org/10.1038/ni.2038
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