TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity
Mark J. McCarron, Julien C. Marie
Mark J. McCarron, Julien C. Marie
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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 4

CD8+ Treg thymic development is defective in the absence of TGF-βR signaling.

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CD8+ Treg thymic development is defective in the absence of TGF-βR signa...
(A) Flow cytometry analysis illustrating the frequency of thymic CD8+ Tregs identified in TGF-βR–KO or TGF-βR-CA mice aged 18 days and their WT controls by gating on CD8SP thymocytes followed by CD44hiCD122+ T cells that express Ly49. Graphs show mean (± SEM) of frequency and total number of thymic CD8+ Tregs from 3 independent experiments with 6 to 8 mice. (B) TGF-βR-II expression on thymic CD8SP subsets in 18-day-old TGF-βR-WT mice. CD44–CD122– (green), CD44+CD122– (red), and CD44+CD122+ (blue) subsets are demonstrated on a representative histogram. Graph represents mean (± SEM) of mean fluorescence intensity (MFI) of TGF-βRII from 3 independent experiments with 3 mice. (C and D) BM from congenic WT mice was combined with BM from either TGF-βR–KO mice (C) or TGF-βR-CA mice (D) and grafted into irradiated recipient Rag-KO mice. The thymus was examined 5 weeks after reconstitution by flow cytometry for the presence of CD8+ Tregs in CD44+CD122+ cells, and the percentage of CD8+ Tregs from each BM are shown. Data are representative of 2 independent experiments with 5 mice. (E) Signal joint TCR excision circles (sjTRECs) were measured by real-time qPCR from genomic DNA of sorted CD8+ Tregs or total CD8+ T cells. Data are presented as mean (± SEM) of expression fold changes, normalized with CD45 expression obtained from triplicate wells. Data are representative of 2 independent experiments with 8 pooled spleens.