Abstract
T follicular helper cells (Tfh cells), which are a prototypic subset of effector CD4+ T cells, regulate the production of high-affinity antibodies by controlling B cells at initial and recall phases. Since the discovery of Tfh cells in human tonsils, many notable studies focusing on Tfh cells have clarified mechanisms underlying Tfh-cell-related physiological and pathological settings. Results of these studies revealed a chief regulatory function of BCL6 in Tfh cells and the involvement of Tfh cells in the pathogenesis of various disorders including autoimmune diseases, allergies and cancers. Further, accumulating evidence has revealed microRNAs (miRNAs) of functional noncoding RNAs (ncRNAs) to be cardinal regulators of Tfh cells during the processes of development, differentiation and plasticity. In this review article, we summarize and discuss the results of recent studies about miRNAs operating Tfh-cell function and their relationships in diseases. Through the window of such functional ncRNAs, the functional significance of Tfh cells in CD4+ T-cell biology is becoming apparent. Studies to determine the complex background of the genetic program of Tfh cells operated by functional RNAs should lead to an understanding of the manifestations of Tfh cells with unidentified pathophysiological relevance.
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References
Vahedi, G., C. Poholek, A., Hand, T. W., Laurence, A., Kanno, Y., O'Shea, J. J. et al. Helper T-cell identity and evolution of differential transcriptomes and epigenomes. Immunol. Rev. 252, 24–40 (2013).
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, 2348–2357 (1986).
Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1564 (1995).
Breitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M. 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).
Harrington, L. E., Hatton, R. D., Mangan, P. R., Turner, H., Murphy, T. L., Murphy, K. M. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Tuomela, S. & Lahesmaa, R. Early T helper cell programming of gene expression in human. Semin. Immunol. 25, 282–290 (2013).
Witte, S., O'Shea, J. J. & Vahedi, G. Super-enhancers: asset management in immune cell genomes. Trends Immunol. 36, 519–526 (2015).
Crotty, S., Johnston, R. J. & Schoenberger, S. P. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat. Immunol. 11, 114–120 (2010).
Nurieva, R. I., Chung, Y., Martinez., G. J., Yang, X. O., Tanaka, S., Matskevitch, T. D. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).
Johnston, R. J., Poholek, A. C., DiToro, D., Yusuf, I., Eto, D., Barnett, B. et al. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325, 1006–1010 (2009).
Ballesteros-Tato, A., Randall, T. D., Lund, F. E., Spolski, R., Leonard, W. J. & León, B. T follicular helper cell plasticity shapes pathogenic T helper 2 cell-mediated immunity to inhaled house dust mite. Immunity 44, 259–273 (2016).
Förster, R., Mattis, A. E., Kremmer, E., Wolf, E., Brem, G. & Lipp, M. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996).
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, 1123–1134 (1999).
Schaerli, P., Willimann, K., Lang, A. B., Lipp, M., Loetscher, P. & Moser, B. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192, 1553–1562 (2000).
Rasheed, A. U., Rahn, H. P., Sallusto, F., Lipp, M. & Müller, 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).
Kerfoot, S. M., Yaari, G., Patel, J. R., Johnson, K. L., Gonzalez, D. G., Kleinstein, S. H. et al. Germinal center B cell and T follicular helper cell development initiates in the interfollicular zone. Immunity. 34, 947–960 (2011).
Kim, C. H., Lim, H. W., Kim, J. R., Rott, L., Hillsamer, P. & Butcher, E. C. Unique gene expression program of human germinal center T helper cells. Blood 104, 1952–1960 (2004).
Havenar-Daughton, C., Lindqvist, M., Heit, A., Wu, J. E., Reiss, S. M., Kendric, K. et al. CXCL13 is a plasma biomarker of germinal center activity. Proc. Natl Acad. Sci. USA 113, 2702–2707 (2016).
Vinuesa, C. G., Linterman, M. A., Yu, D. & MacLennan, I. C. Follicular helper T cells. Annu. Rev. Immunol. 34, 335–368 (2016).
Ueno, H., Banchereau, J. & Vinuesa, C. G. Pathophysiology of T follicular helper cells in humans and mice. Nat. Immunol. 16, 142–152 (2015).
Yamashita, K., Kawata, K., Matsumiya, H., Kamekura, R., Jitsukawa, S., Nagaya, T. et al. Bob1 limits cellular frequency of T follicular helper cells. Eur. J. Immunol. 46, 1361–1370 (2016).
Ueno, H. Human circulating T follicular helper cell subsets in health and disease. J. Clin. Immunol. 36 (Suppl 1), 34–39 (2016).
Morita, R., Schmitt, N., Bentebibel, S. E., Ranganathan, R., Bourdery, L., Zurawski, G. 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).
Kamekura, R., Shigehara, K., Miyajima, S., Jitsukawa, S., Kawata, K., Yamashita, K. et al. Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma. Clin. Immunol. 158, 204–211 (2015).
Fan, X., Jin, T., Zhao, S., Liu, C., Han, J., Jiang, X. et al. Circulating CCR7+ICOS+ Memory T follicular helper cells in patients with multiple sclerosis. PLoS ONE 10, e0134523 (2015).
Szabó, K., Papp, G., Szántó, A., Tarr, T. & Zeher, M. A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren's syndrome and systemic lupus erythematosus. Clin. Exp. Immunol. 183, 76–89 (2016).
Che, Y., Qiu, J., Jin, T., Yin, F., Li, M. & Jiang, Y. Circulating memory T follicular helper subsets, Tfh2 and Tfh17, participate in the pathogenesis of Guillain-Barré syndrome. Sci. Rep. 6, 20963 (2016).
Wollenberg, I., Agua-Doce, A., Hernández, A., Almeida, C., Oliveira, V. G., Faro, J. et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J. Immunol. 187, 4553–4560 (2011).
Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).
Chung, Y., Tanaka, S., Chu, F., Nurieva, R. I., Martinez, G. J., Rawal, S. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).
Wing, J. B., Ise, W., Kurosaki, T. & Sakaguchi, S. Regulatory T cells control antigen-specific expansion of Tfh cell number and humoral immune responses via the coreceptor CTLA-4. Immunity 41, 1013–1025 (2014).
Sage, P. T., Paterson, A. M., Lovitch, S. B. & Sharpe, A. H. The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity 41, 1026–1039 (2014).
Sage, P. T. & Sharpe, A. H. T follicular regulatory cells in the regulation of B cell responses. Trends Immunol. 36, 410–418 (2015).
Nair, S., Boddupalli, C. S., Verma, R., Liu, J., Yang, R., Pastores, G. M. et al. Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation. Blood 125, 1256–1271 (2015).
Cannons, J. L., Lu, K. T. & Schwartzberg, P. L. T follicular helper cell diversity and plasticity. Trends Immunol. 34, 200–207 (2013).
O'Connell, R. M., Rao, D. S. & Baltimore, D. microRNA regulation of inflammatory responses. Annu. Rev. Immunol. 30, 295–312 (2012).
Muljo, S. A., Ansel, K. M., Kanellopoulou, C., Livingston, D. M., Rao, A. & Rajewsky, K. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005).
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, 2005–2017 (2008).
Yu, D., Rao, S., Tsai, L. M., Lee, S. K., He, Y., Sutcliffe, E. L. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).
Baumjohann, D., Kageyama, R., Clingan, J. M., Morar, M. M., Patel, S., de Kouchkovsky, D. et al. The microRNA cluster miR-17-92 promotes TFH cell differentiation and represses subset-inappropriate gene expression. Nat. Immunol. 14, 840–848 (2013).
Baumjohann, D. & Ansel, K. M. microRNA-mediated regulation of T helper cell differentiation and plasticity. Nat. Rev. Immunol. 13, 666–678 (2013).
Liu, X., Chen, X., Zhong, B., Wang, A., Wang, X., Chu, F. et al. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507, 513–518 (2014).
Hatzi, K., Nance, J. P., Kroenke, M. A., Bothwell, M., Haddad, E. K., Melnick, A. et al. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J. Exp. Med. 212, 539–553 (2015).
Baumjohann, D., Okada, T. & Ansel, K. M. Distinct waves of BCL6 expression during T follicular helper cell development. J. Immunol. 187, 2089–2092 (2011).
Takahashi, H., Kanno, T., Nakayamada, S., Hirahara, K., Sciumè, G., Muljo, S. A. et al. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat. Immunol. 13, 587–595 (2012).
Tsuji, M., Komatsu, N., Kawamoto, S., Suzuki, K., Kanagawa, O., Honjo, T. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches. Science 323, 1488–1492 (2009).
Kawamoto, S., Maruya, M., Kato, L. M., Suda, W., Atarashi, K., Doi, Y. et al. Foxp3+ T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).
Yu, T., Liu, L., Li, J., Yan, M., Lin, H., Liu, Y. et al. MiRNA-10a is upregulated in NSCLC and may promote cancer by targeting PTEN. Oncotarget 6, 30239–30250 (2015).
Shrestha, S., Yang, K., Guy, C., Vogel, P., Neale, G. & Chi, H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).
Tanzer, A., Amemiya, C. T., Kim, C. B. & Stadler, P. F. Evolution of microRNAs located within Hox gene clusters. J. Exp. Zool. B Mol. Dev. Evol. 304, 75–85 (2005).
Ørom, U. A., Nielsen, F. C. & Lund, A. H. MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 30, 460–471 (2008).
He, L., Thomson, J. M., Hemann, M. T., Hernando-Monge, E., Mu, D., Goodson, S. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).
Xiao, C., Srinivasan, L., Calado, D. P., Patterson, H. C., Zhang, B., Wang, J. et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat. Immunol. 9, 405–414 (2008).
Kang, S. G., Liu, W. H., Lu, P., Jin, H. Y., Lim, H. W., Shepherd, J. et al. MicroRNAs of the miR-17~92 family are critical regulators of Tfh differentiation. Nat. Immunol. 14, 849–857 (2013).
Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I. C., Sharpe, A. H. et al. The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells. Nat. Immunol. 10, 167–175 (2009).
Gigoux, M., Shang, J., Pak, Y., Xu, M., Choe, J., Mak, T. W. et al. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 106, 20371–20376 (2009).
Stone, E. L., Pepper, M., Katayama, C. D., Kerdiles, Y. M., Lai, C. Y., Emslie, E. et al. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42, 239–251 (2015).
Pratama, A., Srivastava, M., Williams, N. J., Papa, I., Lee, S. K., Dinh, X. T. et al. MicroRNA-146a regulates ICOS-ICOSL signaling to limit accumulation of T follicular helper cells and germinal centers. Nat. Commun. 6, 6436 (2015).
Pratama, A. & Vinuesa, C. G. Control of TFH cell numbers: why and how? Immunol. Cell Biol. 92, 40–48 (2014).
Fenoglio, C., Cantoni, C., De Riz, M., Ridolfi, E., Cortini, F., Serpente, M. et al. Expression and genetic analysis of miRNAs involved in CD4+ cell activation in patients with multiple sclerosis. Neurosci. Lett. 504, 9–12 (2011).
Yang, L., Boldin, M. P., Yu, Y., Liu, C. S., Ea, C. K., Ramakrishnan, P. et al. miR-146a controls the resolution of T cell responses in mice. J. Exp. Med. 209, 1655–1670 (2012).
Taganov, K. D., Boldin, M. P., Chang, K. J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl Acad. Sci. USA 103, 12481–12486 (2006).
Curtale, G., Citarella, F., Carissimi, C., Goldoni, M., Carucci, N., Fulci, V. 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, 265–273 (2010).
Rodriguez, A., Vigorito, E., Clare, S., Warren, M. V., Couttet, P., Soond, D. R. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007).
He, S., Yang, L., Li, D. & Li, M. Kruppel-like factor 2-mediated suppression of microRNA-155 reduces the proinflammatory activation of macrophages. PLoS One 10, e0139060 (2015).
Thai, T. H., Calado, D. P., Casola, S., Ansel, K. M., Xiao, C., Xue, Y. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007).
Hu, R., Kagele, D. A., Huffaker, T. B., Runtsch, M. C., Alexander, M., Liu, J. et al. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity 41, 605–619 (2014).
Eis, P. S., Tam, W., Sun, L., Chadburn, A., Li, Z., Gomez, M. F. et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc. Natl Acad. Sci. USA 102, 3627–3632 (2005).
Mashima, R. Physiological roles of miR-155. Immunology 145, 323–333 (2015).
Yu, D. MicroRNAs in Tfh cells: micromanaging inflammaging. Immunity 41, 509–511 (2014).
Chen, J., Tian, J., Tang, X., Rui, K., Ma, J., Mao, C. et al. MiR-346 regulates CD4+CXCR5+ T cells in the pathogenesis of Graves' disease. Endocrine 49, 752–760 (2015).
Chatzikyriakidou, A., Voulgari, P. V., Georgiou, I. & Drosos, A. A. miRNAs and related polymorphisms in rheumatoid arthritis susceptibility. Autoimmun. Rev. 11, 636–641 (2012).
Ebert, M. S. & Sharp, P. A. Roles for microRNAs in conferring robustness to biological processes. Cell 149, 515–524 (2012).
Ranzani, V., Rossetti, G., Panzeri, I., Arrigoni, A., Bonnal, R. J., Curti, S. et al. The long intergenic noncoding RNA landscape of human lymphocytes highlights the regulation of T cell differentiation by linc-MAF-4. Nat. Immunol. 16, 318–325 (2015).
Acknowledgements
This work was supported by the Japan Society for the Promotion of Science (JSPS) Grants #26670178 (S.I.), #15K10787 (R.K.), #15K20214 (K.K.) and #16K15723 (T.H.).
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Ichimiya, S., Kamekura, R., Kawata, K. et al. Functional RNAs control T follicular helper cells. J Hum Genet 62, 81–86 (2017). https://doi.org/10.1038/jhg.2016.88
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DOI: https://doi.org/10.1038/jhg.2016.88
