RasGRP1 regulates antigen-induced developmental programming by naive CD8 T cells.
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.
Priatel
John J
JJ
Child and Family Research Institute, Vancouver, British Columbia, Canada. jpriatel@interchange.ubc.ca
Chen
Xiaoxi
X
Huang
Yu-Hsuan
YH
Chow
Michael T
MT
Zenewicz
Lauren A
LA
Coughlin
Jason J
JJ
Shen
Hao
H
Stone
James C
JC
Tan
Rusung
R
Teh
Hung Sia
HS
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
D000941:Antigens; D020662:Guanine Nucleotide Exchange Factors; D007376:Interleukin-2; C112278:Rasgrp1 protein, mouse