期刊
JOURNAL OF IMMUNOLOGY
卷 200, 期 2, 页码 586-594出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1701000
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资金
- Chinese National Science Foundation of Distinguished Young Scholars [31525008]
- National Science Foundation of China [81330072]
- National Institutes of Health [AI102187, AI123162, AI095439, AI103162]
- University of Alabama at Birmingham Center for AIDS Research Vaccine Concept grant
- University of Alabama at Birmingham Center for AIDS Research [P30AI027767-26]
T follicular helper (Tfh) cells play an essential role in the formation of germinal centers (GC) and generation of high-affinity Abs. The homing of activated CD4(+) T cells into B cell follicles and the involvement of key costimulatory and coinhibitory molecules are critical in controlling both the initiation and the magnitude of GC responses. Meanwhile, studies have shown that a high number of single clone B cells leads to intraclonal competition, which inhibits the generation of high-affinity Abs. Our previous work has shown that transcription factor Foxp1 is a critical negative regulator of Tfh cell differentiation. In this study, we report that the deletion of Foxp1 leads to a high proportion of activated CD4(+) T cells homing into B cell follicles with faster kinetics, resulting in earlier GC formation. In addition, we show that Foxp1-deficient Tfh cells restore the generation of high-affinity Abs when cotransferred with high numbers of single clone B cells. We find that Foxp1 regulates the expression levels of cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) in activated CD4(+) T cells and that Ctla4 is a direct Foxp1 target. Finally, we demonstrate that CTLA-4 expression on conventional CD4(+) T cells plays a cell-intrinsic role in Tfh cell differentiation in vivo, and CTLA-4 blockade helps abolish the intraclonal competition of B cells in generating high-affinity Abs.
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