鸟嘌呤核苷酸交换因子
生发中心
内化
细胞生物学
生物
CD28
细胞分化
过继性细胞移植
背景(考古学)
T细胞
信号转导
B细胞
细胞
抗体
免疫学
免疫系统
遗传学
基因
古生物学
作者
Lisa Sandner,Marlis Alteneder,Ramona Rica,Barbara Woller,Eleonora Sala,Tobias Frey,Anela Tosevska,Ci Zhu,Moritz Madern,Matarr Khan,Pol Hoffmann,Alexandra Schebesta,Ichiro Taniuchi,Michael Bonelli,Klaus G. Schmetterer,Matteo Iannacone,Mirela Kuka,Wilfried Ellmeier,Shoji Sakaguchi,Ruth Herbst,Nicole Boucheron
摘要
T follicular helper (Tfh) cells are essential for the development of germinal center B cells and high-affinity antibody-producing B cells in humans 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. Mechanistically, adoptive transfer experiments using WT and Rinl-KO naïve CD4+ T cells unraveled T cell–intrinsic GEF-dependent functions of Rinl. Further, 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.
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