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Review Article

Transcriptional and epigenetic regulation of follicular T-helper cells and their role in autoimmunity

, , , &
Pages 71-81 | Received 04 Jul 2016, Accepted 31 Dec 2016, Published online: 21 Feb 2017

References

  • Murphy, K. M. and B. Stockinger. 2010. Effector T cell plasticity: flexibility in the face of changing circumstances. Nat. Immunol. 11: 674–680
  • Rautajoki, K. J., M. K. Kylaniemi, S. K. Raghav, et al. 2008. An insight into molecular mechanisms of human T helper cell differentiation. Ann. Med. 40: 322–335
  • Weaver, C. T., R. D. Hatton, P. R. Mangan, and L.E. Harrington. 2007. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25: 821–852
  • Victora, G. D. and M. C. Nussenzweig. 2012. Germinal centers. Annu. Rev. Immunol. 30: 429–457
  • Chtanova, T., S. G. Tangye, R. Newton, et al. 2004. T follicular helper cells express a distinctive transcriptional profile, reflecting their role as non-Th1/Th2 effector cells that provide help for B cells. J. Immunol. 173: 68–78
  • Kim, C. H., H. W. Lim, J. R. Kim, et al. 2004. Unique gene expression program of human germinal center T helper cells. Blood. 104: 1952–1960
  • Vinuesa, C. G., M. C. Cook, C. Angelucci, et al. 2005. A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity. Nature. 435: 452–458
  • Haynes, N. M., C. D. Allen, R. Lesley, et al. 2007. 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: 5099–5108
  • Schaerli, P., K. Willimann, A. B. Lang, et al. 2000. CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J. Exp. Med. 192: 1553–1562
  • Kim, C. H., L. S. Rott, I. Clark-Lewis, et al. 2001. Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J. Exp. Med. 193: 1373–1381
  • Breitfeld, D., L. Ohl, E. Kremmer, et al. 2000. 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
  • Riella, L. V., A. M. Paterson, A. H. Sharpe, and A. Chandraker. 2012. Role of the PD-1 pathway in the immune response. Am. J. Transplant. 12: 2575–2587
  • Good-Jacobson, K. L., C. G. Szumilas, L. Chen, et al. 2010. PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells. Nat. Immunol. 11: 535–542
  • Dorfman, D. M., J. A. Brown, A. Shahsafaei, and G. J. Freeman. 2006. Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am. J. Surg. Pathol. 30: 802–810
  • Yao, S. and L. Chen. 2014. PD-1 as an immune modulatory receptor. Cancer. J. 20: 262–264
  • Akiba, H., K. Takeda, Y. Kojima, et al. 2005. The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. J. Immunol. 175: 2340–2348
  • Bauquet, A. T., H. Jin, A. M. Paterson, et al. 2009. 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
  • Ma, D. Y. and E. A. Clark. 2009. The role of CD40 and CD154/CD40L in dendritic cells. Semin. Immunol. 21: 265–272
  • Kawabe, T., T. Naka, K. Yoshida, et al. 1994. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity. 1: 167–178
  • Qi, H., J. L. Cannons, F. Klauschen, et al. 2008. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature. 455: 764–769
  • Kashiwakuma, D., A. Suto, Y. Hiramatsu, et al. 2010. B and T lymphocyte attenuator suppresses IL-21 production from follicular Th cells and subsequent humoral immune responses. J. Immunol. 185: 2730–2736
  • Vogelzang, A., H. M. McGuire, D. Yu, et al. 2008. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity. 29: 127–137
  • Nurieva, R. I., Y. Chung, D. Hwang, et al. 2008. 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
  • Vijayanand, P., G. Seumois, L. J. Simpson, et al. 2012. Interleukin-4 production by follicular helper T cells requires the conserved Il4 enhancer hypersensitivity site V. Immunity. 36: 175–187
  • Yusuf, I., R. Kageyama, L. Monticelli, et al. 2010. Germinal center T follicular helper cell IL-4 production is dependent on signaling lymphocytic activation molecule receptor (CD150). J. Immunol. 185: 190–202
  • Johnston, R. J., A. C. Poholek, D. DiToro, et al. 2009. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 325: 1006–1010
  • Nurieva, R. I., Y. Chung, G. J. Martinez, et al. 2009. Bcl6 mediates the development of T follicular helper cells. Science. 325: 1001–1005
  • Yu, D., S. Rao, L. M. Tsai, et al. 2009. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 31: 457–468
  • Hatzi, K., J. P. Nance, M. A. Kroenke, et al. 2015. BCL6 orchestrates Tfh cell differentiation via multiple distinct mechanisms. J. Exp. Med. 212: 539–553
  • Choi, Y. S., R. Kageyama, D. Eto, et al. 2011. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity. 34: 932–946
  • Poholek, A. C., K. Hansen, S. G. Hernandez, et al. 2010. In vivo regulation of Bcl6 and T follicular helper cell development. J. Immunol. 185: 313–326
  • Barish, G. D., R. T. Yu, M. Karunasiri, et al. 2010. Bcl-6 and NF-kappaB cistromes mediate opposing regulation of the innate immune response. Genes. Dev. 24: 2760–2765
  • Liu, X., H. Lu, T. Chen, et al. 2016. Genome-wide analysis identifies Bcl6-controlled regulatory networks during T follicular helper cell differentiation. Cell. Rep. 14: 1735–1747
  • Johnston, R. J., Y. S. Choi, J. A. Diamond, et al. 2012. STAT5 is a potent negative regulator of TFH cell differentiation. J. Exp. Med. 209: 243–250
  • Liu, X., X. Chen, B. Zhong, et al. 2014. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature. 507: 513–518
  • Betz, B. C., K. L. Jordan-Williams, C. Wang, et al. 2010. Batf coordinates multiple aspects of B and T cell function required for normal antibody responses. J. Exp. Med. 207: 933–942
  • Ise, W., M. Kohyama, B. U. Schraml, et al. 2011. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat. Immunol. 12: 536–543
  • Kwon, H., D. Thierry-Mieg, J. Thierry-Mieg, et al. 2009. Analysis of interleukin-21-induced Prdm1 gene regulation reveals functional cooperation of STAT3 and IRF4 transcription factors. Immunity. 31: 941–952
  • Yang, C. Y., J. A. Best, J. Knell, et al. 2011. The transcriptional regulators Id2 and Id3 control the formation of distinct memory CD8+ T cell subsets. Nat. Immunol. 12: 1221–1229
  • Choi, Y. S., J. A. Gullicksrud, S. Xing, et al. 2015. LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat. Immunol. 16: 980–990
  • Xu, L., Y. Cao, Z. Xie, et al. 2015. The transcription factor TCF-1 initiates the differentiation of T(FH) cells during acute viral infection. Nat. Immunol. 16: 991–999
  • Wu, T., H. M. Shin, E. A. Moseman, et al. 2015. TCF1 is required for the T follicular helper cell response to viral infection. Cell. Rep. 12: 2099–2110
  • Feng, X., G. C. Ippolito, L. Tian, et al. 2010. Foxp1 is an essential transcriptional regulator for the generation of quiescent naive T cells during thymocyte development. Blood. 115: 510–518
  • Wang, H., J. Geng, X. Wen, et al. 2014. The transcription factor Foxp1 is a critical negative regulator of the differentiation of follicular helper T cells. Nat. Immunol. 15: 667–675
  • Linterman, M. A., L. Beaton, D. Yu, et al. 2010. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207: 353–363
  • Tan, A. H., S. C. Wong, and K. P. Lam. 2006. Regulation of mouse inducible costimulator (ICOS) expression by Fyn-NFATc2 and ERK signaling in T cells. J. Biol. Chem. 281: 28666–28678
  • Sahoo, A., A. Alekseev, K. Tanaka, et al. 2015. Batf is important for IL-4 expression in T follicular helper cells. Nat. Commun. 6: 7997
  • Ellyard, J. I. and C. G. Vinuesa. 2011. A BATF-ling connection between B cells and follicular helper T cells. Nat. Immunol. 12: 519–520
  • Kroenke, M. A., D. Eto, M. Locci, et al. 2012. Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation. J. Immunol. 188: 3734–3744
  • Huber, M. and M. Lohoff. 2014. IRF4 at the crossroads of effector T-cell fate decision. Eur. J. Immunol. 44: 1886–1895
  • Bollig, N., A. Brustle, K. Kellner, et al. 2012. Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation. Proc. Natl. Acad. Sci. U. S. A. 109: 8664–8669
  • Auderset, F., S. Schuster, N. Fasnacht, et al. 2013. Notch signaling regulates follicular helper T cell differentiation. J. Immunol. 191: 2344–2350
  • Stone, E. L., M. Pepper, C. D. Katayama, et al. 2015. ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity. 42: 239–251
  • Lee, J. Y., C. N. Skon, Y. J. Lee, et al. 2015. The transcription factor KLF2 restrains CD4+ T follicular helper cell differentiation. Immunity. 42: 252–264
  • Choi, Y. S., D. Eto, J. A. Yang, et al. 2013. Cutting edge: STAT1 is required for IL-6-mediated Bcl6 induction for early follicular helper cell differentiation. J. Immunol. 190: 3049–3053
  • Eto, D., C. Lao, D. DiToro, et al. 2011. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS. One. 6: e17739
  • Ma, C. S., D. T. Avery, A. Chan, et al. 2012. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood. 119: 3997–4008
  • Schmitt, N., Y. Liu, S. E. Bentebibel, et al. 2014. The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells. Nat. Immunol. 15: 856–865
  • Nurieva, R., X. O. Yang, G. Martinez, et al. 2007. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature. 448: 480–483
  • Yang, Y., J. Ochando, A. Yopp, et al. 2005. IL-6 plays a unique role in initiating c-Maf expression during early stage of CD4 T cell activation. J. Immunol. 174: 2720–2729
  • Ma, C. S., S. Suryani, D. T. Avery, et al. 2009. Early commitment of naive human CD4(+) T cells to the T follicular helper (T(FH)) cell lineage is induced by IL-12. Immunol. Cell. Biol. 87: 590–600
  • Nakayamada, S., Y. Kanno, H. Takahashi, et al. 2011. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity. 35: 919–931
  • Wei, L., G. Vahedi, H. W. Sun, et al. 2010. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity. 32: 840–851
  • Schmitt, N., J. Bustamante, L. Bourdery, et al. 2013. IL-12 receptor β1 deficiency alters in vivo T follicular helper cell response in humans. Blood. 121: 3375–3385
  • Trinchieri, G., S. Pflanz, and R. A. Kastelein. 2003. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity. 19: 641–644
  • McCarron, M. J. and J. C. Marie. 2014. TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity. J. Clin. Invest. 124: 4375–4386
  • Ballesteros-Tato, A., B. Leon, B. A. Graf, et al. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity. 36: 847–856
  • Bao, Y. and X. Cao. 2016. Epigenetic control of B cell development and B-cell-related immune disorders. Clin. Rev. Allergy. Immunol 50:301–311
  • Kitagawa, Y., J. B. Wing, and S. Sakaguchi. 2015. Transcriptional and epigenetic control of regulatory T cell development. Prog. Mol. Biol. Transl. Sci. 136: 1–33
  • Lin, Q., H. Chauvistre, I. G. Costa, et al. 2015. Epigenetic program and transcription factor circuitry of dendritic cell development. Nucleic. Acids. Res. 43: 9680–9693
  • Wu, H., M. Zhao, A. Yoshimura, et al. 2016. Critical link between epigenetics and transcription factors in the induction of autoimmunity: a comprehensive review. Clin. Rev. Allergy. Immunol 50:333–344
  • Sellars, M., J. R. Huh, K. Day, et al. 2015. Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages. Nat. Immunol. 16: 746–754
  • Nagata, D. E., H. A. Ting, K. A. Cavassani, et al. 2015. Epigenetic control of Foxp3 by SMYD3 H3K4 histone methyltransferase controls iTreg development and regulates pathogenic T-cell responses during pulmonary viral infection. Mucosal. Immunol. 8: 1131–1143
  • Bernstein, B. E., A. Meissner, and E. S. Lander. 2007. The mammalian epigenome. Cell. 128: 669–681
  • Rothbart, S. B. and B. D. Strahl. 2014. Interpreting the language of histone and DNA modifications. Biochim. Biophys. Acta. 1839: 627–643
  • Renaudineau, Y. and P. Youinou. 2011. Epigenetics and autoimmunity, with special emphasis on methylation. Keio. J. Med. 60: 10–16
  • Black, J. C., C. Van Rechem, and J. R. Whetstine. 2012. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell. 48: 491–507
  • Cook, K. D., K. B. Shpargel, J. Starmer, et al. 2015. T follicular helper cell-dependent clearance of a persistent virus infection requires T cell expression of the histone demethylase UTX. Immunity. 43: 703–714
  • de Wit, J., T. Jorritsma, M. Makuch, et al. 2015. Human B cells promote T-cell plasticity to optimize antibody response by inducing coexpression of T(H)1/T(FH) signatures. J. Allergy. Clin. Immunol. 135: 1053. 60
  • Ballesteros-Tato, A., T. D. Randall, F. E. Lund, et al. 2016. T follicular helper cell plasticity shapes pathogenic T helper 2 cell-mediated immunity to inhaled house dust mite. Immunity. 44: 259–273
  • Zhang, X., Y. Zhang, X. Liu, et al. 2016. Direct quantitative detection for cell-free miR-155 in urine: a potential role in diagnosis and prognosis for non-muscle invasive bladder cancer. Oncotarget. 7: 3255–3266
  • Chung, Y., S. Tanaka, F. Chu, et al. 2011. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17: 983–988
  • Lu, K. T., Y. Kanno, J. L. Cannons, et al. 2011. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity. 35: 622–632
  • Cannons, J. L., K. T. Lu, and P. L. Schwartzberg. 2013. T follicular helper cell diversity and plasticity. Trends. Immunol. 34: 200–207
  • Gerner, M. Y., P. Torabi-Parizi, and R. N. Germain. 2015. Strategically localized dendritic cells promote rapid T cell responses to lymph-borne particulate antigens. Immunity. 42: 172–185
  • Fife, B. T., K. E. Pauken, T. N. Eagar, et al. 2009. Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat. Immunol. 10: 1185–1192
  • Linterman, M. A., W. Pierson, S. K. Lee, et al. 2011. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17: 975–982
  • Sage, P. T., L. M. Francisco, C. V. Carman, and A. H. Sharpe. 2013. The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat. Immunol. 14: 152–161
  • Vaeth, M., G. Muller, D. Stauss, et al. 2014. Follicular regulatory T cells control humoral autoimmunity via NFAT2-regulated CXCR5 expression. J. Exp. Med. 211: 545–561
  • Chang, J. H., H. Hu, J. Jin, et al. 2014. TRAF3 regulates the effector function of regulatory T cells and humoral immune responses. J. Exp. Med. 211: 137–151
  • Sage, P. T., D. Alvarez, J. Godec, et al. 2014. Circulating T follicular regulatory and helper cells have memory-like properties. J. Clin. Invest. 124: 5191–5204
  • Sage, P. T., C. L. Tan, G. J. Freeman, et al. 2015. Defective TFH cell function and increased TFR cells contribute to defective antibody production in aging. Cell. Rep. 12: 163–171
  • Tsuji, M., N. Komatsu, S. Kawamoto, et al. 2009. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science. 323: 1488–1492
  • Chen, C. Z., L. Li, H. F. Lodish, and D. P. Bartel. 2004. MicroRNAs modulate hematopoietic lineage differentiation. Science. 303: 83–86
  • Fabian, M. R., N. Sonenberg, and W. Filipowicz. 2010. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79: 351–379
  • Kang, S. G., W. H. Liu, P. Lu, et al. 2013. MicroRNAs of the miR-17∼92 family are critical regulators of T(FH) differentiation. Nat. Immunol. 14: 849–857
  • Hu, R., D. A. Kagele, T. B. Huffaker, et al. 2014. miR-155 promotes T follicular helper cell accumulation during chronic, low-grade inflammation. Immunity. 41: 605–619
  • Choi, J. Y., J. H. Ho, S. G. Pasoto, et al. 2015. Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity. Arthritis. Rheumatol. 67: 988–999
  • Wong, C. K., L. C. Lit, L. S. Tam, et al. 2008. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin. Immunol. 127: 385–393
  • Koenig, K. F., I. Groeschl, S. S. Pesickova, et al. 2012. Serum cytokine profile in patients with active lupus nephritis. Cytokine. 60: 410–416
  • Huang, X., J. Hua, N. Shen, and S. Chen. 2007. Dysregulated expression of interleukin-23 and interleukin-12 subunits in systemic lupus erythematosus patients. Mod. Rheumatol. 17: 220–223
  • Hansel, A., C. Gunther, W. Baran, et al. 2013. Human 6-sulfo LacNAc (slan) dendritic cells have molecular and functional features of an important pro-inflammatory cell type in lupus erythematosus. J. Autoimmun. 40: 1–8
  • Liarski, V. M., N. Kaverina, A. Chang, et al. 2014. Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci. Transl. Med. 6: 230ra46
  • Jacquemin, C., N. Schmitt, C. Contin-Bordes, et al. 2015. OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity. 42: 1159–1170
  • Croft, M. 2010. Control of immunity by the TNFR-related molecule OX40 (CD134). Annu. Rev. Immunol. 28: 57–78
  • Lan, Y., B. Luo, J. L. Wang, et al. 2014. The association of interleukin-21 polymorphisms with interleukin-21 serum levels and risk of systemic lupus erythematosus. Gene. 538: 94–98
  • Jarvinen, T. M., A. Hellquist, S. Koskenmies, et al. 2010. Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Exp. Dermatol. 19: 123–131
  • Tsuchiya, N., I. Ito, and A. Kawasaki. 2010. Association of IRF5, STAT4 and BLK with systemic lupus erythematosus and other rheumatic diseases. Nihon. Rinsho. Meneki. Gakkai. Kaishi. 33: 57–65
  • Graham, R. R., S. V. Kozyrev, E. C. Baechler, et al. 2006. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat. Genet. 38: 550–555
  • Lessard, C. J., I. Adrianto, J. A. Ice, et al. 2012. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am. J. Hum. Genet. 90: 648–660
  • Yoshida, Y., R. Yoshimi, H. Yoshii, et al. 2014. The transcription factor IRF8 activates integrin-mediated TGF-beta signaling and promotes neuroinflammation. Immunity. 40: 187–198
  • Qi, J. H., J. Qi, L. N. Xiang, and G. Nie. 2015. Association between IL-21 polymorphism and systemic lupus erythematosus: a meta-analysis. Genet. Mol. Res. 14: 9595–9603
  • Engelmann, R., J. Brandt, M. Eggert, et al. 2008. IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA. Rheumatology (Oxford). 47: 1489–1492
  • Liu, R., Q. Wu, D. Su, et al. 2012. A regulatory effect of IL-21 on T follicular helper-like cell and B cell in rheumatoid arthritis. Arthritis. Res. Ther. 14: R255
  • Liao, J., G. Liang, S. Xie, et al. 2012. CD40L demethylation in CD4(+) T cells from women with rheumatoid arthritis. Clin. Immunol. 145: 13–18
  • Meguro, K., K. Suzuki, J. Hosokawa, et al. 2015. Role of Bcl-3 in the development of follicular helper T cells and in the pathogenesis of rheumatoid arthritis. Arthritis. Rheumatol. 67: 2651–2660
  • Zhang, Y., Y. Li, T. T. Lv, et al. 2015. Elevated circulating Th17 and follicular helper CD4(+) T cells in patients with rheumatoid arthritis. APMIS. 123: 659–666
  • Compston, A. and A. Coles. 2008. Multiple sclerosis. Lancet. 372: 1502–1517
  • Krumbholz, M. and E. Meinl. 2014. B cells in MS and NMO: pathogenesis and therapy. Semin. Immunopathol. 36: 339–350
  • Piccio, L., R. T. Naismith, K. Trinkaus, et al. 2010. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis. Arch. Neurol. 67: 707–714
  • Tzartos, J. S., M. J. Craner, M. A. Friese, et al. 2011. IL-21 and IL-21 receptor expression in lymphocytes and neurons in multiple sclerosis brain. Am. J. Pathol. 178: 794–802
  • Fan, X., T. Jin, S. Zhao, et al. circulating CCR7 + ICOS + memory T follicular helper cells in patients with multiple sclerosis. PLoS. One. 2015. 10: e0134523
  • Romme Christensen, J., L. Bornsen, R. Ratzer, et al. 2013. Systemic inflammation in progressive multiple sclerosis involves follicular T-helper, Th17- and activated B-cells and correlates with progression. PLoS. One. 8: e57820
  • Peters, A., L. A. Pitcher, J. M. Sullivan, et al. 2011. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity. 35: 986–996
  • Spiering, R., B. Margry, C. Keijzer, et al. 2015. DEC205+ dendritic cell-targeted tolerogenic vaccination promotes immune tolerance in experimental autoimmune arthritis. J. Immunol. 194: 4804–4813
  • Kosmaczewska, A. 2014. Low-dose interleukin-2 therapy: a driver of an imbalance between immune tolerance and autoimmunity. Int. J. Mol. Sci. 15: 18574–18592
  • He, J., X. Zhang, Y. Wei, et al. 2016. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat. Med. 22: 991–993
  • Liu, R., X. Li, Z. Zhang, et al. 2015. Allogeneic mesenchymal stem cells inhibited T follicular helper cell generation in rheumatoid arthritis. Sci. Rep. 5: 12777

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