title: RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells.
abstract: Ag encounter by naive CD8 T cells initiates a developmental program consisting of cellular proliferation, changes in gene expression, and the formation of effector and memory T cells. The strength and duration of TCR signaling are known to be important parameters regulating the differentiation of naive CD8 T cells, although the molecular signals arbitrating these processes remain poorly defined. The Ras-guanyl nucleotide exchange factor RasGRP1 has been shown to transduce TCR-mediated signals critically required for the maturation of developing thymocytes. To elucidate the role of RasGRP1 in CD8 T cell differentiation, in vitro and in vivo experiments were performed with 2C TCR transgenic CD8 T cells lacking RasGRP1. In this study, we report that RasGRP1 regulates the threshold of T cell activation and Ag-induced expansion, at least in part, through the regulation of IL-2 production. Moreover, RasGRP1(-/-) 2C CD8 T cells exhibit an anergic phenotype in response to cognate Ag stimulation that is partially reversible upon the addition of exogenous IL-2. By contrast, the capacity of IL-2/IL-2R interactions to mediate Ras activation and CD8 T cell expansion and differentiation appears to be largely RasGRP1-independent. Collectively, our results demonstrate that RasGRP1 plays a selective role in T cell signaling, controlling the initiation and duration of CD8 T cell immune responses.
authors.affiliation: Child and Family Research Institute, Vancouver, British Columbia, Canada. jpriatel@interchange.ubc.ca
authors.forename: John J
authors.initials: JJ
authors.lastname: Priatel
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Chen
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Huang
authors.forename: Michael T
authors.initials: MT
authors.lastname: Chow
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Zenewicz
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Coughlin
authors.forename: Hao
authors.initials: H
authors.lastname: Shen
authors.forename: James C
authors.initials: JC
authors.lastname: Stone
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
authors.forename: Hung Sia
authors.initials: HS
authors.lastname: Teh
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D019076:Transgenes
chemical_list: D000941:Antigens; D020662:Guanine Nucleotide Exchange Factors; D007376:Interleukin-2; C112278:Rasgrp1 protein, mouse