Foxp1 negatively regulates Tfh cell differentiation and germinal center responses by controlling cell migration and CTLA-4

• Published in: The Journal of immunology (1950) 2017-12, Vol.200 (2), p.586-594
• Main Authors: Shi, Bi, Geng, Jianlin, Wang, Yin-Hu, Wei, Hairong, Walters, Beth, Li, Wei, Luo, Xuerui, Stevens, Anna, Pittman, Melanie, Li, Bin, Thompson, Sunnie R., Hu, Hui
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1701000

T follicular helper (Tfh) cells play an essential role in the formation of germinal center (GC) and generation of high-affinity antibodies. The homing of activated CD4 + T cells into B cell follicles and the involvement of key co-stimulatory/co-inhibitory 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 lead to intra-clonal competition, which inhibits the generation of high-affinity antibodies. Our previous work has shown that transcription factor Foxp1 is a critical negative regulator of Tfh cell differentiation. Here we report that the deletion of Foxp1 leads a high proportion of activated CD4 + T cells homing into B cell follicles with a faster kinetics, resulting in earlier GC formation. In addition, we show that Foxp1-deficient Tfh cells restore the generation of high-affinity antibodies when co-transferred with high numbers of single clone B cells. We find that Foxp1 regulates the expression levels of 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 intra-clonal competition of B cells in generating high-affinity antibodies.