The guanine nucleotide exchange factor Rin-like acts as a gatekeeper for T follicular helper cell differentiation via regulating CD28 signaling

Abstract

T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody producing B-cells in human and mice. Here, we identify the guanine nucleotide exchange factor (GEF) Rin-like (Rinl) as a negative regulator of Tfh generation. Loss of Rinl leads to an increase of Tfh in aging, upon in vivo immunization and acute LCMV Armstrong infection in mice, and in human CD4+ T cell in vitro cultures. Further, adoptive transfer experiments using WT and Rinl-KO naive CD4+ T cells unraveled T cell-intrinsic functions of Rinl. Mechanistically, Rinl regulates CD28 internalization and signaling, thereby shaping CD4+ T cell activation and differentiation. Thus, our results identify the GEF Rinl as a negative regulator of global Tfh differentiation in an immunological context and species-independent manner, and furthermore connect Rinl with CD28 internalization and signaling pathways in CD4+ T cells, demonstrating for the first-time the importance of endocytic processes for Tfh differentiation. HighlightsO_LIRinl-KO CD4+ T cells show increased Tfh differentiation in a context independent manner C_LIO_LIThe regulation of Tfh differentiation is T cell-intrinsic C_LIO_LIRinl controls CD28 endocytosis and shapes Tfh-specific CD28 signal transduction C_LIO_LIHuman Tfh differentiation is regulated by Rinl C_LI