Department of Microbiology, Miami University, Oxford, OH.
Department of Microbiology, Miami University, Oxford, OH
J Immunol. 2021 Dec 1;207(11):2688-2698. doi: 10.4049/jimmunol.2100218. Epub 2021 Oct 25.
Regulation of BCR signaling has important consequences for generating effective Ab responses to pathogens and preventing production of autoreactive B cells during development. Currently defined functions of Fc receptor-like (FCRL) 1 include positive regulation of BCR-induced calcium flux, proliferation, and Ab production; however, the mechanistic basis of FCRL1 signaling and its contributions to B cell development remain undefined. Molecular characterization of FCRL1 signaling shows phosphotyrosine-dependent associations with GRB2, GRAP, SHIP-1, and SOS1, all of which can profoundly influence MAPK signaling. In contrast with previous characterizations of FCRL1 as a strictly activating receptor, we discover a role for FCRL1 in suppressing ERK activation under homeostatic and BCR-stimulated conditions in a GRB2-dependent manner. Our analysis of B cells in mice shows that ERK suppression by FCRL1 is associated with a restriction in the number of cells surviving splenic maturation in vivo. The capacity of FCRL1 to modulate ERK activation presents a potential for FCRL1 to be a regulator of peripheral B cell tolerance, homeostasis, and activation.
BCR 信号的调节对产生针对病原体的有效 Ab 反应以及在发育过程中防止产生自身反应性 B 细胞具有重要意义。目前定义的 Fc 受体样（FCRL）1 功能包括对 BCR 诱导的钙通量、增殖和 Ab 产生的正调节；然而，FCRL1 信号转导的机制基础及其对 B 细胞发育的贡献仍未定义。FCRL1 信号转导的分子特征显示与 GRB2、GRAP、SHIP-1 和 SOS1 有依赖于磷酸酪氨酸的关联，所有这些都可以深刻地影响 MAPK 信号转导。与之前将 FCRL1 严格定义为激活受体的描述相反，我们发现 FCRL1 在依赖于 GRB2 的方式下，在体内稳态和 BCR 刺激条件下抑制 ERK 激活。我们对 小鼠 B 细胞的分析表明，FCRL1 通过抑制 ERK 激活与体内存活的细胞数量减少有关，在脾脏成熟过程中。FCRL1 调节 ERK 激活的能力表明，FCRL1 有可能成为外周 B 细胞耐受、稳态和激活的调节剂。
