Abstract
The production of antibody is precisely controlled during the germinal center (GC) reaction. This process is dependent on the help from follicular T helper (Tfh) cells to germinal center (GC) B cells and is regulated by regulatory follicular T helper (Tfr) cells. How Tfr cells develop and how their suppressive activity functions are not well understood. Here, we found that Stat3 is indispensible for Tfr cell differentiation. After immunization with Sheep Red Blood Cells (SRBC), the loss of Tfr cells caused by deletion of Stat3 in Treg cells does not affect the size of Tfh or GC B cell population, but rather leads to strongly enhanced production of antigen-specific IgG1 and IgG2b. In Peyer’s patches (PPs) in the gut, we found that Stat3 expression in Treg cells is also required for Tfr cell formation to commensal organisms. However, loss of Tfr cells in the gut did not affect the numbers of Tfh cells and GC B cells, nor affect IgG1 or IgA switching by GC B cells. Overall, our study has uncovered unique roles of Stat3 in Tfr cell differentiation and the regulation of the antibody response.
Highlights
To provide host protection against pathogens, CD4+ T cells differentiate into several distinct lineages that confer specific effector functions
We calculated the relative decrease levels for Tfh and Tfr cells due to deletion of Stat3, and found that the average loss of Tfr cells (>80% decrease) is much higher than the average loss for Tfh cells (~40% decrease). These results suggest that Stat3 in CD4 T cells are required for normal Tfh and Tfr cell differentiation, but that Tfr cells are more dependent on Stat3 than Tfh cells
The differentiation defect in Tfr cell differentiation is Treg cell intrinsic The population of germinal centers (GCs) B cells was dramatically decreased in Stat3CD4KO mice [26] and GC B cells are important for Tfh cell differentiation and maintenance [27]
Summary
To provide host protection against pathogens, CD4+ T cells differentiate into several distinct lineages that confer specific effector functions. Follicular T helper (Tfh) cells are a T helper cell lineage whose major function is to help B cells form germinal centers (GCs) and produce high-affinity antibodies (Abs) [1, 2]. Cytokine receptor signaling activates specific transcription factor pathways, and the Stat4-Tbet, Stat6-Gata and Stat3-Rorγt pathways promote Th1, Th2 and Th17 cell differentiation respectively [3]. Tfh cells are driven by the transcription repressor Bcl, which is induced downstream of Stat, Stat or Stat activation [4,5,6,7,8]. The proper regulation of Tfh and GC B cell responses is essential both for normal immune function and for preventing autoimmune disease
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