MicroRNA-mediated regulation of T helper cell differentiation and plasticity

Journal name:
Nature Reviews Immunology
Volume:
13,
Pages:
666–678
Year published:
DOI:
doi:10.1038/nri3494
Published online

Abstract

CD4+ T helper (TH) cells regulate appropriate cellular and humoral immune responses to a wide range of pathogens and are central to the success of vaccines. However, their dysregulation can cause allergies and autoimmune diseases. The CD4+ T cell population is characterized not only by a range of distinct cell subsets, such as TH1, TH2 and TH17 cells, regulatory T cells and T follicular helper cells — each with specific functions and gene expression programmes — but also by plasticity between the different TH cell subsets. In this Review, we discuss recent advances and emerging ideas about how microRNAs — small endogenously expressed oligonucleotides that modulate gene expression — are involved in the regulatory networks that determine TH cell fate decisions and that regulate their effector functions.

At a glance

Figures

  1. miRNA-mediated regulation of T helper cell activation.
    Figure 1: miRNA-mediated regulation of T helper cell activation.

    a | MicroRNAs (miRNAs) are important regulators of effector T cell differentiation, including T cell activation, proliferation and the acquisition of effector functions such as cytokine production (left panel). The genetic ablation of key molecules of the miRNA biogenesis pathway in CD4+ T cells highlighted the importance of miRNAs in these processes. The activation of miRNA-deficient CD4+ T cells results in increased and aberrant cytokine production and decreased cell proliferation (right panel). b | A mechanistic overview of the participation of miRNAs in regulatory networks that control T cell activation, the expansion of the T cell population and effector T cell differentiation is shown. The T cell receptor (TCR) signalling cascade activates nuclear factor of activated T cells (NFAT) and nuclear factor-κB (NF-κB), both of which induce the upregulation of miR-155 expression. miR-155 targets SH2 domain-containing inositol polyphosphate 5′ phosphatase 1 (Ship1) and suppressor of cytokine signalling 1 (Socs1), and promotes T cell activation and population expansion. NF-κB signalling also induces the expression of miR-146a, which inhibits T cell activation and population expansion through a negative feedback loop involving the miR-146a target genes TNF receptor-associated factor 6 (Traf6) and interleukin-1 receptor-associated kinase 1 (Irak1). Mammalian target of rapamycin (mTOR) signalling results in accelerated miRNA turnover and promotes T cell survival and proliferation partly through MYC-induced miR-17~92 expression. The high levels of expression of miR-125b in human naive CD4+ T cells impede T cell differentiation by repressing T cell effector genes, including interferon-γ (IFNG), IL2RB and PRDM1 (the gene encoding B lymphocyte-induced maturation protein 1 (BLIMP1)). The downregulation of inhibitory phosphatases such as dual-specificity protein phosphatase 5 (Dusp5), Dusp6, protein tyrosine phosphatase non-receptor type 22 (Ptpn22) and SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) by miR-181a increases TCR signalling. IL-2-induced miR-182 expression interferes with T cell population expansion by targeting the transcription factor forkhead box protein O1 (Foxo1). It is worth noting that specific miRNAs are both regulated targets and upstream regulators of signalling pathways that control T cell behaviour. AGO2, Argonaute 2; Bim, BCL-2-interacting mediator of cell death; DC, dendritic cell; Pten, phosphatase and tensin homologue.

  2. miRNA-mediated regulation of IFN[gamma] production.
    Figure 2: miRNA-mediated regulation of IFNγ production.

    Interferon-γ (IFNγ) production and signalling in T helper 1 (TH1) cells is regulated by several microRNAs (miRNAs) at distinct levels. The lineage-determining T-box transcription factor T-bet induces expression of the TH1 cell hallmark cytokine IFNγ. T-bet is induced by T cell receptor (TCR) signalling, by interleukin-12 receptor (IL-12R) signalling via signal transducer and activator of transcription 4 (STAT4), and by IFNγ receptor (IFNGR) signalling in a positive feedback loop via STAT1. miR-146a directly targets Stat1 and the nuclear factor-κΒ (NF-κB) signalling molecules TNF receptor-associated factor 6 (Traf6) and IL-1R-associated kinase 1 (Irak1). TCR activation induces the expression of miR-155, which in turn downregulates the negative regulators of cytokine signalling SH2 domain-containing inositol polyphosphate 5′ phosphatase 1 (Ship1) and suppressor of cytokine signalling 1 (Socs1). However, miR-155 has also been proposed to induce the downregulation of Ifngr1. miR-29 limits TH1 cell differentiation and IFNγ production by targeting the mRNAs encoding T-bet, eomesodermin (Eomes) and IFNγ itself. DC, dendritic cell.

  3. miRNA-mediated regulation of TReg cell function and plasticity.
    Figure 3: miRNA-mediated regulation of TReg cell function and plasticity.

    a | The regulatory T (TReg) cell-specific expression of microRNAs (miRNAs) is required to restrain effector T cell responses. In the absence of miRNA expression in TReg cells — for example, because of a deficiency of Dicer or Drosha — TReg cells fail to maintain tolerance, which results in autoimmunity. b | Examples of the miRNA-mediated pathways that contribute to the regulation of TReg cell function and plasticity are shown. miR-146a expression in TReg cells prevents interferon-γ (IFNγ)-mediated T helper 1 (TH1) cell pathology through the inhibition of its direct target signal transducer and activator of transcription 1 (Stat1). miR-155 promotes TReg cell maintenance by inhibiting suppressor of cytokine signalling 1 (Socs1), which is a negative regulator of interleukin-2 receptor (IL-2R) signalling. Retinoic acid-induced miR-10a expression suppresses the conversion of TReg cells into T follicular helper (TFH) cells under certain conditions by the inhibition of TFH cell-associated transcriptional repressor B cell lymphoma-6 (Bcl6) and the nuclear co-repressor 2 (Ncor2). Although the miR-17~92 cluster has been shown to restrain different aspects of TReg cell biology, the precise mechanisms by which miR-17~92 regulates these processes remain largely unknown.

References

  1. Mosmann, T. R., Cherwinski, H., Bond, M. W., Giedlin, M. A. & Coffman, R. L. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol. 136, 23482357 (1986).
  2. Zhou, L., Chong, M. M. & Littman, D. R. Plasticity of CD4+ T cell lineage differentiation. Immunity 30, 646655 (2009).
  3. Locksley, R. M. Nine lives: plasticity among T helper cell subsets. J. Exp. Med. 206, 16431646 (2009).
  4. Murphy, K. M. & Stockinger, B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nature Immunol. 11, 674680 (2010).
  5. O'Shea, J. J. & Paul, W. E. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327, 10981102 (2010).
  6. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nature Rev. Immunol. 9, 91105 (2009).
  7. Ansel, K. M., Djuretic, I., Tanasa, B. & Rao, A. Regulation of Th2 differentiation and Il4 locus accessibility. Annu. Rev. Immunol. 24, 607656 (2006).
  8. Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K. & O'Shea, J. J. Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu. Rev. Immunol. 30, 707731 (2012).
  9. Zhu, J., Yamane, H. & Paul, W. E. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28, 445489 (2010).
  10. Ansel, K. M., Lee, D. U. & Rao, A. An epigenetic view of helper T cell differentiation. Nature Immunol. 4, 616623 (2003).
  11. Bartel, D. P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215233 (2009).
  12. Fabian, M. R., Sonenberg, N. & Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351379 (2010).
  13. Krol, J., Loedige, I. & Filipowicz, W. The widespread regulation of microRNA biogenesis, function and decay. Nature Rev. Genet. 11, 597610 (2010).
  14. Mendell, J. T. & Olson, E. N. MicroRNAs in stress signaling and human disease. Cell 148, 11721187 (2012).
  15. Hoefig, K. P. & Heissmeyer, V. MicroRNAs grow up in the immune system. Curr. Opin. Immunol. 20, 281287 (2008).
  16. Ceribelli, A., Satoh, M. & Chan, E. K. MicroRNAs and autoimmunity. Curr. Opin. Immunol. 24, 686691 (2012).
  17. O'Connell, R. M., Rao, D. S., Chaudhuri, A. A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nature Rev. Immunol. 10, 111122 (2010).
  18. Nakayamada, S., Takahashi, H., Kanno, Y. & O'Shea, J. J. Helper T cell diversity and plasticity. Curr. Opin. Immunol. 24, 297302 (2012).
  19. Xiao, C. & Rajewsky, K. MicroRNA control in the immune system: basic principles. Cell 136, 2636 (2009).
  20. Belver, L., Papavasiliou, F. N. & Ramiro, A. R. MicroRNA control of lymphocyte differentiation and function. Curr. Opin. Immunol. 23, 368373 (2011).
  21. Jeker, L. T. & Bluestone, J. A. Small RNA regulators of T cell-mediated autoimmunity. J. Clin. Immunol. 30, 347357 (2010).
  22. Monticelli, S. et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 6, R71 (2005).
    This study was the first to systematically profile miRNA expression in the mouse haematopoietic system.
  23. Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 14011414 (2007).
  24. Barski, A. et al. Chromatin poises miRNA- and protein-coding genes for expression. Genome Res. 19, 17421751 (2009).
  25. Rossi, R. L. et al. Distinct microRNA signatures in human lymphocyte subsets and enforcement of the naive state in CD4+ T cells by the microRNA miR-125b. Nature Immunol. 12, 796803 (2011).
    This study uses high-throughput miRNA profiling to establish miRNA expression in human lymphocyte subsets.
  26. Kuchen, S. et al. Regulation of microRNA expression and abundance during lymphopoiesis. Immunity 32, 828839 (2010).
    In this paper, high-throughput sequencing technology is used to comprehensively characterize the miRNome in many immune cell types.
  27. Muljo, S. A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261269 (2005).
    This study provides the first evidence that miRNAs are important regulators of TH cell differentiation.
  28. Cobb, B. S. et al. A role for Dicer in immune regulation. J. Exp. Med. 203, 25192527 (2006).
  29. Tian, L. et al. Loss of T cell microRNA provides systemic protection against autoimmune pathology in mice. J. Autoimmun. 38, 3948 (2012).
  30. Chong, M. M., Rasmussen, J. P., Rudensky, A. Y. & Littman, D. R. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205, 20052017 (2008).
  31. Steiner, D. F. et al. MicroRNA-29 regulates T-box transcription factors and interferon-γ production in helper T cells. Immunity 35, 169181 (2011).
  32. Bronevetsky, Y. et al. T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J. Exp. Med. 210, 417432 (2013).
  33. Sandberg, R., Neilson, J. R., Sarma, A., Sharp, P. A. & Burge, C. B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 16431647 (2008).
  34. Ma, F. et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nature Immunol. 12, 861869 (2011).
  35. Smith, K. M. et al. miR-29ab1 deficiency identifies a negative feedback loop controlling Th1 bias that is dysregulated in multiple sclerosis. J. Immunol. 189, 15671576 (2012).
    References 31, 34 and 35 show that miR-29 is an important regulator of IFNγ production in TH1 cells.
  36. Li, Q. J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147161 (2007).
  37. Ebert, P. J., Jiang, S., Xie, J., Li, Q. J. & Davis, M. M. An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nature Immunol. 10, 11621169 (2009).
  38. Henao-Mejia, J. et al. The MicroRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell ontogenesis and lymphocyte development and homeostasis. Immunity 38, 984997 (2013).
  39. Fragoso, R. et al. Modulating the strength and threshold of NOTCH oncogenic signals by mir-181a-1/b-1. PLoS Genet. 8, e1002855 (2012).
  40. Zietara, N. et al. Critical role for miR-181a/b-1 in agonist selection of invariant natural killer T cells. Proc. Natl Acad. Sci. USA 110, 74077412 (2013).
  41. Li, G. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nature Med. 18, 15181524 (2012).
  42. Palin, A. C., Ramachandran, V., Acharya, S. & Lewis, D. B. Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the MicroRNA miR-181a. J. Immunol. 190, 26822691 (2013).
  43. Rusca, N. et al. miR-146a and NF-κB1 regulate mast cell survival and T lymphocyte differentiation. Mol. Cell. Biol. 32, 44324444 (2012).
  44. Curtale, G. et al. An emerging player in the adaptive immune response: microRNA-146a is a modulator of IL-2 expression and activation-induced cell death in T lymphocytes. Blood 115, 265273 (2010).
  45. Zhao, J. L. et al. NF-κB dysregulation in microRNA-146a-deficient mice drives the development of myeloid malignancies. Proc. Natl Acad. Sci. USA 108, 91849189 (2011).
  46. Yang, L. et al. miR-146a controls the resolution of T cell responses in mice. J. Exp. Med. 209, 16551670 (2012).
  47. Wu, T. et al. Temporal expression of microRNA cluster miR-17-92 regulates effector and memory CD8+ T-cell differentiation. Proc. Natl Acad. Sci. USA 109, 99659970 (2012).
  48. Xiao, C. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nature Immunol. 9, 405414 (2008).
    This paper shows that the overexpression of the miR-17~92 cluster in lymphocytes leads to lymphoproliferative disease and autoimmunity.
  49. Loeb, G. B. et al. Transcriptome-wide miR-155 binding map reveals widespread noncanonical MicroRNA targeting. Mol. Cell 48, 760770 (2012).
    This study is a transcriptome-wide analysis of miRNA-binding sites that shows an unexpectedly high frequency of functional non-canonical target sites.
  50. Iliopoulos, D., Jaeger, S. A., Hirsch, H. A., Bulyk, M. L. & Struhl, K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 39, 493506 (2010).
  51. Huffaker, T. B. et al. Epistasis between microRNAs 155 and 146a during T cell-mediated antitumor immunity. Cell Rep. 2, 16971709 (2012).
    This paper shows epistasis between miR-155 and miR-146a in T cell-mediated antitumour immunity.
  52. Banerjee, A., Schambach, F., DeJong, C. S., Hammond, S. M. & Reiner, S. L. Micro-RNA-155 inhibits IFN-γ signaling in CD4+ T cells. Eur. J. Immunol. 40, 225231 (2010).
  53. Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604608 (2007).
  54. Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608611 (2007).
    References 53 and 54 were the first to show that genetic disruption of a single miRNA in vivo can have adverse effects on immune cell homeostasis and function.
  55. O'Connell, R. M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607619 (2010).
  56. Oertli, M. et al. MicroRNA-155 is essential for the T cell-mediated control of Helicobacter pylori infection and for the induction of chronic Gastritis and Colitis. J. Immunol. 187, 35783586 (2011).
  57. Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 1325 (2013).
  58. Thiele, S., Wittmann, J., Jack, H. M. & Pahl, A. miR-9 enhances IL-2 production in activated human CD4+ T cells by repressing Blimp-1. Eur. J. Immunol. 42, 21002108 (2012).
  59. Seddiki, N. et al. The microRNA-9/B-lymphocyte-induced maturation protein-1/IL-2 axis is differentially regulated in progressive HIV infection. Eur. J. Immunol. 43, 510520 (2013).
  60. Martins, G. A., Cimmino, L., Liao, J., Magnusdottir, E. & Calame, K. Blimp-1 directly represses Il2 and the Il2 activator Fos, attenuating T cell proliferation and survival. J. Exp. Med. 205, 19591965 (2008).
  61. Stittrich, A. B. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nature Immunol. 11, 10571062 (2010).
  62. Lu, L. F. et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142, 914929 (2010).
  63. Lu, L. F. et al. Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30, 8091 (2009).
  64. Jiang, S. et al. Molecular dissection of the miR-17-92 cluster's critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood 118, 54875497 (2011).
  65. Lazarevic, V. & Glimcher, L. H. T-bet in disease. Nature Immunol. 12, 597606 (2011).
  66. Lu, T. X., Munitz, A. & Rothenberg, M. E. MicroRNA-21 is up-regulated in allergic airway inflammation and regulates IL-12p35 expression. J. Immunol. 182, 49945002 (2009).
  67. Lu, T. X. et al. MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-γ pathway, Th1 polarization, and the severity of delayed-type hypersensitivity. J. Immunol. 187, 33623373 (2011).
  68. Jeker, L. T. & Bluestone, J. A. MicroRNA regulation of T-cell differentiation and function. Immunol. Rev. 253, 6581 (2013).
  69. Beaulieu, A. M. et al. MicroRNA function in NK-cell biology. Immunol. Rev. 253, 4052 (2013).
  70. Allen, J. E. & Maizels, R. M. Diversity and dialogue in immunity to helminths. Nature Rev. Immunol. 11, 375388 (2011).
  71. Locksley, R. M. Asthma and allergic inflammation. Cell 140, 777783 (2010).
  72. Paul, W. E. & Zhu, J. How are TH2-type immune responses initiated and amplified? Nature Rev. Immunol. 10, 225235 (2010).
  73. Sawant, D. V., Wu, H., Kaplan, M. H. & Dent, A. L. The Bcl6 target gene microRNA-21 promotes Th2 differentiation by a T cell intrinsic pathway. Mol. Immunol. 54, 435442 (2013).
  74. Guerau-de-Arellano, M. et al. Micro-RNA dysregulation in multiple sclerosis favours pro-inflammatory T-cell-mediated autoimmunity. Brain 134, 35783589 (2011).
  75. Seumois, G. et al. An integrated nano-scale approach to profile miRNAs in limited clinical samples. Am. J. Clin. Exp. Immunol. 1, 7089 (2012).
  76. Solberg, O. D. et al. Airway epithelial miRNA expression is altered in asthma. Am. J. Respir. Crit. Care Med. 186, 965974 (2012).
  77. Mattes, J., Collison, A., Plank, M., Phipps, S. & Foster, P. S. Antagonism of microRNA-126 suppresses the effector function of TH2 cells and the development of allergic airways disease. Proc. Natl Acad. Sci. USA 106, 1870418709 (2009).
  78. Collison, A. et al. Altered expression of microRNA in the airway wall in chronic asthma: miR-126 as a potential therapeutic target. BMC Pulm. Med. 11, 29 (2011).
  79. Collison, A., Mattes, J., Plank, M. & Foster, P. S. Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment. J. Allergy Clin. Immunol. 128, 160167.e4 (2011).
  80. Polikepahad, S. et al. Proinflammatory role for let-7 microRNAs in experimental asthma. J. Biol. Chem. 285, 3013930149 (2010).
  81. Kumar, M. et al. Let-7 microRNA-mediated regulation of IL-13 and allergic airway inflammation. J. Allergy Clin. Immunol. 128, 10771085.e10 (2011).
  82. Swaminathan, S. et al. Differential regulation of the Let-7 family of microRNAs in CD4+ T cells alters IL-10 expression. J. Immunol. 188, 62386246 (2012).
  83. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485517 (2009).
  84. Weaver, C. T., Elson, C. O., Fouser, L. A. & Kolls, J. K. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu. Rev. Pathol. 8, 477512 (2013).
  85. Thamilarasan, M., Koczan, D., Hecker, M., Paap, B. & Zettl, U. K. MicroRNAs in multiple sclerosis and experimental autoimmune encephalomyelitis. Autoimmun. Rev. 11, 174179 (2012).
  86. Du, C. et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nature Immunol. 10, 12521259 (2009).
  87. Takahashi, H. et al. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nature Immunol. 13, 587595 (2012).
  88. Oestreich, K. J., Huang, A. C. & Weinmann, A. S. The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J. Exp. Med. 208, 10011013 (2011).
  89. Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 10011005 (2009).
  90. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457468 (2009).
  91. Lazarevic, V. et al. T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt. Nature Immunol. 12, 96104 (2011).
  92. Murugaiyan, G., Beynon, V., Mittal, A., Joller, N. & Weiner, H. L. Silencing microRNA-155 ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 187, 22132221 (2011).
  93. Mycko, M. P. et al. MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc. Natl Acad. Sci. USA 109, e1248e1257 (2012).
  94. Basu, R., Hatton, R. D. & Weaver, C. T. The Th17 family: flexibility follows function. Immunol. Rev. 252, 89103 (2013).
  95. Ansel, K. M., McHeyzer-Williams, L. J., Ngo, V. N., McHeyzer-Williams, M. G. & Cyster, J. G. In vivo-activated CD4 T cells upregulate CXC chemokine receptor 5 and reprogram their response to lymphoid chemokines. J. Exp. Med. 190, 11231134 (1999).
  96. 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, 15451552 (2000).
  97. Schaerli, P. et al. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 15531562 (2000).
  98. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621663 (2011).
  99. Craft, J. E. Follicular helper T cells in immunity and systemic autoimmunity. Nature Rev. Rheumatol. 8, 337347 (2012).
  100. Johnston, R. J. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 10061010 (2009).
  101. Choi, Y. S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932946 (2011).
  102. Baumjohann, D., Okada, T. & Ansel, K. M. Cutting edge: distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 187, 20892092 (2011).
  103. Haynes, N. M. et al. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J. Immunol. 179, 50995108 (2007).
  104. Deenick, E. K. et al. Follicular helper T cell differentiation requires continuous antigen presentation that is independent of unique B cell signaling. Immunity 33, 241253 (2010).
  105. Baumjohann, D. et al. Persistent antigen and germinal center B cells sustain T follicular helper cell responses and phenotype. Immunity 38, 596605 (2013).
  106. Baumjohann, D. et al. The microRNA cluster miR-17~92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nature Immunol. 14, 840848 (2013).
  107. Vinuesa, C. G. et al. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature 435, 452458 (2005).
  108. Yu, D. et al. Roquin represses autoimmunity by limiting inducible T-cell co-stimulator messenger RNA. Nature 450, 299303 (2007).
  109. Glasmacher, E. et al. Roquin binds inducible costimulator mRNA and effectors of mRNA decay to induce microRNA-independent post-transcriptional repression. Nature Immunol. 11, 725733 (2010).
  110. Kang, S. G. et al. MicroRNAs of the miR-17~92 family are critical regulators of TFH differentiation. Nature Immunol. 14, 849857 (2013).
  111. Pepper, M., Pagan, A. J., Igyarto, B. Z., Taylor, J. J. & Jenkins, M. K. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity 35, 583595 (2011).
  112. Nakayamada, S. et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity 35, 919931 (2011).
  113. Oestreich, K. J., Mohn, S. E. & Weinmann, A. S. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nature Immunol. 13, 405411 (2012).
  114. Sallusto, F., Geginat, J. & Lanzavecchia, A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol. 22, 745763 (2004).
  115. Wing, K. & Sakaguchi, S. Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nature Immunol. 11, 713 (2010).
  116. Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531564 (2012).
  117. Zhou, X. et al. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J. Exp. Med. 205, 19831991 (2008).
  118. Liston, A., Lu, L. F., O'Carroll, D., Tarakhovsky, A. & Rudensky, A. Y. Dicer-dependent microRNA pathway safeguards regulatory T cell function. J. Exp. Med. 205, 19932004 (2008).
    References 30, 117 and 118 describe that miRNA expression in TReg cells is required to prevent autoimmunity.
  119. Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936940 (2007).
  120. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931935 (2007).
  121. de Kouchkovsky, D. et al. miR-17~92 regulates interleukin-10 production by Tregs and control of experimental autoimmune encephalomyelitis. J. Immunol. http://dx.doi.org/10.4049/jimmunol.1203567 (2013).
  122. Jeker, L. T. et al. MicroRNA 10a marks regulatory T cells. PLoS ONE 7, e36684 (2012).
  123. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 14881492 (2009).
  124. Ansel, K. M. RNA regulation of the immune system. Immunol. Rev. 253, 511 (2013).
  125. Pagani, M. et al. Role of microRNAs and long-non-coding RNAs in CD4+ T-cell differentiation. Immunol. Rev. 253, 8296 (2013).
  126. Dooley, J., Linterman, M. A. & Liston, A. MicroRNA regulation of T-cell development. Immunol. Rev. 253, 5364 (2013).
  127. Petrocca, F. & Lieberman, J. Promise and challenge of RNA interference-based therapy for cancer. J. Clin. Oncol. 29, 747754 (2011).
  128. Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 16851694 (2013).
  129. Peer, D. A daunting task: manipulating leukocyte function with RNAi. Immunol. Rev. 253, 185197 (2013).
  130. Fabian, M. R. & Sonenberg, N. The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nature Struct. Mol. Biol. 19, 586593 (2012).
  131. Leshkowitz, D., Horn-Saban, S., Parmet, Y. & Feldmesser, E. Differences in microRNA detection levels are technology and sequence dependent. RNA 19, 527538 (2013).
  132. Kozomara, A. & Griffiths-Jones, S. miRBase: integrating microRNA annotation and deep-sequencing data. Nucleic Acids Res. 39, D152D157 (2011).
  133. Friedman, R. C., Farh, K. K., Burge, C. B. & Bartel, D. P. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92105 (2009).
  134. Hsu, S. D. et al. miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res. 39, D163D169 (2011).
  135. Prosser, H. M., Koike-Yusa, H., Cooper, J. D., Law, F. C. & Bradley, A. A resource of vectors and ES cells for targeted deletion of microRNAs in mice. Nature Biotech. 29, 840845 (2011).
  136. Park, C. Y. et al. A resource for the conditional ablation of microRNAs in the mouse. Cell Rep. 1, 385391 (2012).
  137. Brown, B. D. & Naldini, L. Exploiting and antagonizing microRNA regulation for therapeutic and experimental applications. Nature Rev. Genet. 10, 578585 (2009).
  138. Thomas, M., Lieberman, J. & Lal, A. Desperately seeking microRNA targets. Nature Struct. Mol. Biol. 17, 11691174 (2010).
  139. Chi, S. W., Zang, J. B., Mele, A. & Darnell, R. B. Argonaute HITS-CLIP decodes microRNA–mRNA interaction maps. Nature 460, 479486 (2009).
  140. Hafner, M. et al. Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP. Cell 141, 129141 (2010).

Download references

Author information

Affiliations

  1. Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, California 94143, USA.

    • Dirk Baumjohann &
    • K. Mark Ansel

Competing interests statement

The authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Dirk Baumjohann

    Dirk Baumjohann is currently a postdoctoral fellow in the laboratory of K. Mark Ansel at the University of California, San Francisco, California, USA. He received his Ph.D. in cell biology and immunology from the University of Bern, Switzerland, for work with Federica Sallusto at the Institute for Research in Biomedicine in Bellinzona, Switzerland. His recent studies focus on understanding how microRNAs and transcription factors regulate T helper cell differentiation.

  • K. Mark Ansel

    K. Mark Ansel is Assistant Professor of microbiology & immunology in the Sandler Asthma Basic Research Center at the University of California, San Francisco (UCSF), California, USA. He completed his Ph.D. in biomedical sciences in Jason Cyster's laboratory at UCSF, and conducted postdoctoral research with Anjana Rao at Harvard Medical School, Cambridge, Massachusetts, USA. His laboratory studies microRNA-mediated regulation in the immune system. K. Mark Ansel's homepage.

Additional data