Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice

Hao Wu, Yuxin Chen, Hong Liu, Lin Lin Xu, Paula Teuscher, Shixia Wang, Shan Lu, Alexander Dent

Research output: Contribution to journalArticle

39 Citations (Scopus)

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+ CXCR5hi PD-1hi CD25low TIGIThigh 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.

Original languageEnglish (US)
JournalEuropean Journal of Immunology
DOIs
StateAccepted/In press - 2016

Fingerprint

Regulatory T-Lymphocytes
Helper-Inducer T-Lymphocytes
Immunoglobulin G
Cytokines
Germinal Center
B-Lymphocytes
Antibody Formation
T-Lymphocytes
Antigens
Interleukin-10
Immunoglobulin A
Interferons
Population
HIV-1
Immunization
Vaccines
Antibodies
DNA
Genes

Keywords

  • Antibody
  • Bcl6
  • Follicular T cells
  • Germinal Center Response
  • Regulatory T cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice. / Wu, Hao; Chen, Yuxin; Liu, Hong; Xu, Lin Lin; Teuscher, Paula; Wang, Shixia; Lu, Shan; Dent, Alexander.

In: European Journal of Immunology, 2016.

Research output: Contribution to journalArticle

@article{32cd48b7dc164a39a3e8121146640dbf,
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+ CXCR5hi PD-1hi CD25low TIGIThigh 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.",
keywords = "Antibody, Bcl6, Follicular T cells, Germinal Center Response, Regulatory T cells",
author = "Hao Wu and Yuxin Chen and Hong Liu and Xu, {Lin Lin} and Paula Teuscher and Shixia Wang and Shan Lu and Alexander Dent",
year = "2016",
doi = "10.1002/eji.201546094",
language = "English (US)",
journal = "European Journal of Immunology",
issn = "0014-2980",
publisher = "Wiley-VCH Verlag",

}

TY - JOUR

T1 - Follicular regulatory T cells repress cytokine production by follicular helper T cells and optimize IgG responses in mice

AU - Wu, Hao

AU - Chen, Yuxin

AU - Liu, Hong

AU - Xu, Lin Lin

AU - Teuscher, Paula

AU - Wang, Shixia

AU - Lu, Shan

AU - Dent, Alexander

PY - 2016

Y1 - 2016

N2 - 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+ CXCR5hi PD-1hi CD25low TIGIThigh 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.

AB - 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+ CXCR5hi PD-1hi CD25low TIGIThigh 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.

KW - Antibody

KW - Bcl6

KW - Follicular T cells

KW - Germinal Center Response

KW - Regulatory T cells

UR - http://www.scopus.com/inward/record.url?scp=84960391287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84960391287&partnerID=8YFLogxK

U2 - 10.1002/eji.201546094

DO - 10.1002/eji.201546094

M3 - Article

C2 - 26887860

AN - SCOPUS:84960391287

JO - European Journal of Immunology

JF - European Journal of Immunology

SN - 0014-2980

ER -