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* Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada; and
Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
The Ras-guanyl nucleotide exchange factor RasGRP1 is an important link between TCR-mediated signaling and the activation of Ras and its downstream effectors. RasGRP1 is especially critical for the survival and differentiation of developing thymocytes whereas negative selection of thymocytes bearing an autoreactive TCR appears to be RasGRP1 independent. Despite apparently normal central tolerance, RasGRP1–/– mice spontaneously acquire an acutely activated and proliferating CD4 T cell population that exhibits characteristics of T cell exhaustion, including strong expression of programmed cell death-1. To elucidate the basis for RasGRP1–/– CD4 T cell immune activation, we initiated a series of adoptive transfer experiments. Remarkably, the copious amounts of cytokines and self-Ags present in hosts made lymphopenic through irradiation failed to induce the majority of RasGRP1–/– CD4 T cells to enter cell cycle. However, their infusion into either congenitally T cell- or T/B cell-deficient recipients resulted in robust proliferation and L-selectin down-regulation. These findings imply that the activation and proliferation of RasGRP1–/– CD4 T cells may be dependent on their residence in a chronically immunocompromised environment. Accordingly, bacterial and viral challenge experiments revealed that RasGRP1–/– mice possess a weakened immune system, exhibiting a T cell-autonomous defect in generating pathogen-specific T cells and delayed pathogen clearance. Collectively, our study suggests that chronic T cell immunodeficiency in RasGRP1–/– mice may be responsible for CD4 T cell activation, proliferation, and exhaustion.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grant MOP-77547 from the Canadian Institutes of Health Research (CIHR; to H.-S.T.). J.J.P. was funded in part by a CIHR fellowship.
2 Current address: Department of Pathology and Laboratory Medicine, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
3 Address correspondence and reprint requests to Dr. Hung-Sia Teh, Department of Microbiology and Immunology, Life Sciences Centre, University of British Columbia, Room 3509, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3. E-mail address: teh{at}interchange.ubc.ca
4 Abbreviations used in this paper: PD-1, programmed cell death 1; PD-L1, PD-1 ligand 1; DP, double-positive thymocyte; SP, single-positive thymocyte; LCMV, lymphocytic choriomeningitis virus; LN, lymph node; MLN, mesenteric LN; SLE, systemic lupus erythematosus; LLO, listeriolysin O.
This article has been cited by other articles:
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  X. Chen, J. J. Priatel, M. T. Chow, and H.-S. Teh Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice J. Immunol., May 1, 2008; 180(9): 5973 - 5982. [Abstract] [Full Text] [PDF]
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