title: Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice.
abstract: Follicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) cells, modulate this process. However, Tfr-cell function in the GC is not well understood. Here, we define Tfr cells as a CD4(+) Foxp3(+) CXCR5(hi) PD-1(hi) CD25(low) TIGIT(high) T-cell population. Furthermore, we have used a novel mouse model ("Bcl6FC") to delete the Bcl6 gene in Foxp3(+) T cells and thus specifically deplete Tfr cells. Following immunization, Bcl6FC mice develop normal Tfh- and GCB-cell populations. However, Bcl6FC mice produce altered antigen-specific antibody responses, with reduced titers of IgG and significantly increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV-1 gp120 "prime-boost" vaccine model. In an autoimmune lupus model, we observed strongly elevated anti-DNA IgA titers in Bcl6FC mice. Additionally, Tfh cells from Bcl6FC mice consistently produce higher levels of Interferon-γ, IL-10 and IL-21. Loss of Tfr cells therefore leads to highly abnormal Tfh-cell and GCB-cell responses. Overall, our study has uncovered unique regulatory roles for Tfr cells in the GC response.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Xu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Paula
authors.initials: P
authors.lastname: Teuscher
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Shixia
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D015551:Autoimmunity; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004247:DNA / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis; D018858:Germinal Center / Q000276:immunology*; D015483:HIV Antibodies / Q000096:biosynthesis / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology / Q000378:metabolism; D007070:Immunoglobulin A / Q000096:biosynthesis / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D051379:Mice; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000172:deficiency / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology; D014611:Vaccination; D000098546:Interleukin-21
chemical_list: C490010:Bcl6 protein, mouse; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C556062:IL10 protein, mouse; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D016753:Interleukin-10; D007371:Interferon-gamma; D004247:DNA; D000098546:Interleukin-21
keywords: Antibody; Bcl6; Follicular T cells; Germinal Center Response; Regulatory T cells