Deficiency in T Follicular Regulatory Cells Promotes Autoimmunity

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2018 Jan 31

PMID 29378778

Citations 99

Authors

Weiwei Fu

Xindong Liu

Xiang Lin

Han Feng

Lin Sun

Shuran Li

Hairong Chen

Hong Tang

Liwei Lu

Wei Jin

Chen Dong

Affiliations

Soon will be listed here.

Abstract

T follicular regulatory (Tfr) cells are a new subset of regulatory T (T reg) cells localized in the germinal center to limit the humoral response. Until now, the physiological function of Tfr cells has been largely unknown. In this study, we developed a mouse to analyze the function of Tfr cells in immune and autoimmune responses. These mice exhibited enhanced immunity to influenza virus; moreover, mice developed late-onset spontaneous autoimmune diseases, affecting the salivary glands with lymphocyte infiltration and antibody deposition. In a mouse experimental Sjögren's syndrome model, ablation of in T reg cells greatly enhanced disease development. Conversely, mice were protected in the model. Thus, our study indicates that Tfr cells control autoimmune diseases and can be targeted in infectious and autoimmune disease.

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References

Sage P, Tan C, Freeman G, Haigis M, Sharpe A . Defective TFH Cell Function and Increased TFR Cells Contribute to Defective Antibody Production in Aging. Cell Rep. 2015; 12(2):163-71. PMC: 4504745. DOI: 10.1016/j.celrep.2015.06.015. View

Jandl C, Liu S, Canete P, Warren J, Hughes W, Vogelzang A . IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2. Nat Commun. 2017; 8:14647. PMC: 5357862. DOI: 10.1038/ncomms14647. View

Gomez-Martin D, Diaz-Zamudio M, Romo-Tena J, Ibarra-Sanchez M, Alcocer-Varela J . Follicular helper T cells poise immune responses to the development of autoimmune pathology. Autoimmun Rev. 2010; 10(6):325-30. DOI: 10.1016/j.autrev.2010.11.007. View

Sage P, Paterson A, Lovitch S, Sharpe A . The coinhibitory receptor CTLA-4 controls B cell responses by modulating T follicular helper, T follicular regulatory, and T regulatory cells. Immunity. 2014; 41(6):1026-39. PMC: 4309019. DOI: 10.1016/j.immuni.2014.12.005. View

Snapper C, Paul W . Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987; 236(4804):944-7. DOI: 10.1126/science.3107127. View

Wing J, 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. 2014; 41(6):1013-25. DOI: 10.1016/j.immuni.2014.12.006. View

Zotos D, Coquet J, Zhang Y, Light A, DCosta K, Kallies A . IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010; 207(2):365-78. PMC: 2822601. DOI: 10.1084/jem.20091777. View

Lin X, Rui K, Deng J, Tian J, Wang X, Wang S . Th17 cells play a critical role in the development of experimental Sjögren's syndrome. Ann Rheum Dis. 2014; 74(6):1302-10. DOI: 10.1136/annrheumdis-2013-204584. View

Miyazaki M, Miyazaki K, Chen S, Itoi M, Miller M, Lu L . Id2 and Id3 maintain the regulatory T cell pool to suppress inflammatory disease. Nat Immunol. 2014; 15(8):767-76. PMC: 4365819. DOI: 10.1038/ni.2928. View

10.

Takahashi Y, Ohta H, Takemori T . Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity. 2001; 14(2):181-92. DOI: 10.1016/s1074-7613(01)00100-5. View

11.

Aloulou M, Carr E, Gador M, Bignon A, Liblau R, Fazilleau N . Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells. Nat Commun. 2016; 7:10579. PMC: 4738360. DOI: 10.1038/ncomms10579. View

12.

Victora G, Dominguez-Sola D, Holmes A, Deroubaix S, Dalla-Favera R, Nussenzweig M . Identification of human germinal center light and dark zone cells and their relationship to human B-cell lymphomas. Blood. 2012; 120(11):2240-8. PMC: 3447782. DOI: 10.1182/blood-2012-03-415380. View

13.

Sage P, Ron-Harel N, Juneja V, Sen D, Maleri S, Sungnak W . Suppression by T cells leads to durable and selective inhibition of B cell effector function. Nat Immunol. 2016; 17(12):1436-1446. PMC: 5502675. DOI: 10.1038/ni.3578. View

14.

Crotty S . T follicular helper cell differentiation, function, and roles in disease. Immunity. 2014; 41(4):529-42. PMC: 4223692. DOI: 10.1016/j.immuni.2014.10.004. View

15.

Wing J, Kitagawa Y, Locci M, Hume H, Tay C, Morita T . A distinct subpopulation of CD25 T-follicular regulatory cells localizes in the germinal centers. Proc Natl Acad Sci U S A. 2017; 114(31):E6400-E6409. PMC: 5547636. DOI: 10.1073/pnas.1705551114. View

16.

Sage P, Francisco L, Carman C, Sharpe A . The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood. Nat Immunol. 2012; 14(2):152-61. PMC: 3788614. DOI: 10.1038/ni.2496. View

17.

Vaeth M, Eckstein M, Shaw P, Kozhaya L, Yang J, Berberich-Siebelt F . Store-Operated Ca(2+) Entry in Follicular T Cells Controls Humoral Immune Responses and Autoimmunity. Immunity. 2016; 44(6):1350-64. PMC: 4917422. DOI: 10.1016/j.immuni.2016.04.013. View

18.

Victora G, Schwickert T, Fooksman D, Kamphorst A, Meyer-Hermann M, Dustin M . Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell. 2010; 143(4):592-605. PMC: 3035939. DOI: 10.1016/j.cell.2010.10.032. View

19.

Sage P, Alvarez D, Godec J, von Andrian U, Sharpe A . Circulating T follicular regulatory and helper cells have memory-like properties. J Clin Invest. 2014; 124(12):5191-204. PMC: 4348955. DOI: 10.1172/JCI76861. View

20.

Johnston R, Poholek A, DiToro D, Yusuf I, Eto D, Barnett B . Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science. 2009; 325(5943):1006-10. PMC: 2766560. DOI: 10.1126/science.1175870. View