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Preferential Development of CD4 and CD8 T Regulatory Cells in RasGRP1-Deficient Mice¹

Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada

RasGRP1 and Sos are two Ras-guanyl-nucleotide exchange factors that link TCR signal transduction to Ras and MAPK activation. Recent studies demonstrate positive selection of developing thymocytes is crucially dependent on RasGRP1, whereas negative selection of autoreactive thymocytes appears to be RasGRP1 independent. However, the role of RasGRP1 in T regulatory (Treg) cell development and function is unknown. In this study, we characterized the development and function of CD4⁺CD25⁺Foxp3⁺ and CD8⁺CD44^highCD122⁺ Treg lineages in RasGRP1^–/– mice. Despite impaired CD4 Treg cell development in the thymus, the periphery of RasGRP1^–/– mice contained significantly increased frequencies of CD4⁺Foxp3⁺ Treg cells that possessed a more activated cell surface phenotype. Furthermore, on a per cell basis, CD4⁺Foxp3⁺ Treg cells from mutant mice are more suppressive than their wild-type counterparts. Our data also suggest that the lymphopenic environment in the mutant mice plays a dominant role of favored peripheral development of CD4 Treg cells. These studies suggest that whereas RasGRP1 is crucial for the intrathymic development of CD4 Treg cells, it is not required for their peripheral expansion and function. By contrast to CD4⁺CD25⁺Foxp3⁺ T cells, intrathymic development of CD8⁺CD44^highCD122⁺ Treg cells is unaffected by the RasGRP1^–/– mutation. Moreover, RasGRP1^–/– mice contained greater numbers of CD8⁺CD44^highCD122⁺ T cells in the spleen, relative to wild-type mice. Activated CD8 Treg cells from RasGRP1^–/– mice retained their ability to synthesize IL-10 and suppress the proliferation of wild-type CD8⁺CD122^– T cells, albeit at a much lower efficiency than wild-type CD8 Treg cells.

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¹ This work was supported by grants from the Canadian Institutes of Health Research (Grant MOP-77547) and the National Cancer Institute of Canada with funds from the Terry Fox Foundation (Grant no. 016342) to H.-S.T.

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 Science Centre, University of British Columbia, Room 3509, 2350 Health Science Mall, Vancouver, B.C., Canada V6T 1Z3. E-mail address: teh{at}interchange.ubc.ca

⁴ Abbreviations used in this paper: Treg, T regulatory; DAG, diacylglycerol; SP, single positive.