STAT5 protein negatively regulates T follicular helper (Tfh) cell generation and function.
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.
Department of Immunology, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Roza I
RI
Nurieva
Andrew
A
Podd
Yuhong
Y
Chen
Andrei M
AM
Alekseev
Mei
M
Yu
Xiaopeng
X
Qi
Hua
H
Huang
Renren
R
Wen
Junmei
J
Wang
Haiyan S
HS
Li
Stephanie S
SS
Watowich
Hai
H
Qi
Chen
C
Dong
Demin
D
Wang
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D051379:Mice; D000074462:Positive Regulatory Domain I-Binding Factor 1; D050799:STAT5 Transcription Factor / Q000172:deficiency / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D015854:Up-Regulation
C513258:Prdm1 protein, mouse; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1