TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity
Mark J. McCarron, Julien C. Marie
Mark J. McCarron, Julien C. Marie
Published October 1, 2014; First published August 26, 2014
Citation Information: J Clin Invest. 2014;124(10):4375-4386. https://doi.org/10.1172/JCI76179.
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Research Article Immunology

TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity

Abstract

T follicular helper (Tfh) cells contribute to the establishment of humoral immunity by controlling the delivery of helper signals to activated B cells; however, Tfh development must be restrained, as aberrant accumulation of these cells is associated with positive selection of self-reactive germinal center B cells and autoimmunity in both humans and mice. Here, we show that TGF-β signaling in T cells prevented Tfh cell accumulation, self-reactive B cell activation, and autoantibody production. Using mice with either T cell–specific loss or constitutive activation of TGF-β signaling, we demonstrated that TGF-β signaling is required for the thymic maturation of CD44+CD122+Ly49+CD8+ regulatory T cells (Tregs), which induce Tfh apoptosis and thus regulate this cell population. Moreover, peripheral Tfh cells escaping TGF-β control were resistant to apoptosis, exhibited high levels of the antiapoptotic protein BCL2, and remained refractory to regulation by CD8+ Tregs. The unrestrained accumulation of Tfh cells in the absence of TGF-β was dependent on T cell receptor engagement and required B cells. Together, these data indicate that TGF-β signaling restrains Tfh cell accumulation and B cell–associated autoimmunity and thereby controls self-tolerance.

Authors

Mark J. McCarron, Julien C. Marie

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Figure 1

Unrestrained accumulation of Tfh cells in the absence of TGF-β signaling in T cells.

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Unrestrained accumulation of Tfh cells in the absence of TGF-β signaling...
(A) Mean (± SEM) representation of ELISA titration of dsDNA-specific IgG from serum of TGF-βR–KO and TGF-βR-WT mice at different ages from 4 independent experiments with a total of 8 mice per group. (B) Representative images of IgG staining on kidney sections from TGF-βR-WT and TGF-βR–KO mice aged 20 days from 3 independent experiments with a total of 5 animals per group. Original magnification, ×10 and ×40, as indicated in the panels. (C) Flow cytometry analysis of PD-1 and CXCR5 expression on CD4+ B220– FOXP3– T cells from pLNs of 18-day-old TGF-βR–KO and TGF-βR-WT mice. The percentage of Tfh cells are indicated on the plots. (D) Graphs illustrate the mean of frequency and total numbers of Tfh cells (± SEM) of 4 independent experiments with 12 mice per group. (E) Cytometry analysis of Fas and GL7 expression on B cells from 18-day-old mice. The percentage of GC B cells are indicated on the contour plots. (F) Graph represents mean (± SEM) of the frequency of GC B cells from 11 mice from 3 independent experiments. (G) Tfh cells in the pLNs of TGF-βR-DN mice at different ages. (H) Graphs represent mean (± SEM) of the percentage of Tfh cells from at least 3 independent experiments with 4 to 8 mice per time point. (I) Percentage of GL7+Fas+ B cells at different ages. (J) Graphs represent the mean (± SEM) of the percentage of GC B cells from 3 independent experiments with 4 to 8 animals per time point.