Abstract
Recent work has identified a new subset of CD4(+) T cells named as Tfh cells that are localized in germinal centers and critical in germinal center formation. Tfh cell differentiation is regulated by IL-6 and IL-21, possibly via STAT3 factor, and B cell lymphoma 6 (Bcl6) is specifically expressed in Tfh cells and required for their lineage specification. In the current study, we characterized the role of STAT5 in Tfh cell development. We found that a constitutively active form of STAT5 effectively inhibited Tfh differentiation by suppressing the expression of Tfh-associated factors (CXC motif) receptor 5 (CXCR5), musculoaponeurotic fibrosarcoma (c-Maf), Bcl6, basic leucine zipper transcription factor ATF-like (Batf), and IL-21, and STAT5 deficiency greatly enhanced Tfh gene expression. Importantly, STAT5 regulated the expression of Tfh cell suppressor factor B lymphocyte-induced maturation protein 1 (Blimp-1); STAT5 deficiency impaired Blimp-1 expression and resulted in elevated expression of Tfh-specific genes. Similarly, inhibition of IL-2 potentiated Tfh generation, associated with dampened Blimp-1 expression; Blimp-1 overexpression inhibited Tfh gene expression in Stat5-deficient T cells, suggesting that the IL-2/STAT5 axis functions to regulate Blimp-1 expression. In vivo, deletion of STAT5 in CD4(+) T cells resulted in enhanced development of Tfh cells and germinal center B cells and led to an impairment of B cell tolerance in a well defined mouse tolerance model. Taken together, this study demonstrates that STAT5 controls Tfh differentiation.
Highlights
Tfh cells regulate B cell-mediated humoral immunity
We have shown that T cells activated in vitro in the presence of IL-6 or IL-21 but without TGF, IL-4, and IFN-␥ signaling preferentially acquire Tfh gene expression and function to promote humoral immunity in vivo [6]
To determine the role of STAT5 in Tfh generation, naive CD4ϩ T cells from OT-II mice activated with Ova peptide and irradiated antigen-presenting cells under neutral or IL-6 treatment (IL-6, anti-TGF, anti-IL-4, and antiIFN-␥) conditions were infected with a constitutively active form of STAT5 or a vector control retrovirus that contains an IRES-GFP
Summary
Results: STAT5 regulated Blimp-1 expression, and STAT5 deficiency in CD4ϩ T cells resulted in an increase of Tfh generation and an impairment of B cell tolerance. A new subset of CD4ϩ T cells, named Tfh cells, has emerged as a major player in B cell-mediated humoral immunity, especially in the germinal center reactions [1,2,3,4]. In addition to CXCR5, additional Tfh cell markers have been reported, such as inducible costimulatory molecule, IL-21, and the transcription factors c-Maf, Batf, and Bcl6 [1, 5,6,7,8,9,10,11,12]. As well as others, recently reported that Bcl, a transcriptional factor selectively
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