The role of RasGRPs in regulation of lymphocyte proliferation

Immunology Letters
Jason CoughlinJ C Stone

Abstract

RasGRP1 links TCR signaling to Ras in T cells, while both RasGRP1 and RasGRP3 link BCR signaling to Ras in B cells. T cells deficient in RasGRP1 have defective proliferative responses as do B cells deficient in both RasGRP1 and RasGRP3, confirming the importance of Ras activation in lymphocyte proliferation. While aged Rasgrp1-/- mice develop late-onset autoimmunity characterized by splenomegaly and the presence of anti-nuclear antibodies (ANA), the additional loss of RasGRP3 expression inhibits this phenotype. We show here that the autoimmunity in Rasgrp1-/- mice is T cell dependent. Compared to wildtype, Rasgrp1-/- T cells induce greater in vitro B cell proliferation that is due, at least in part, to increased production of interleukin-4 (IL-4). Rasgrp1 Rasgrp3 double mutant B cells are less responsive to this T cell stimulation. The reduced double mutant B cell proliferative response was paralleled by decreased induction of cyclin D2 upon stimulation with IL-4 and anti-IgM. Taken together these results suggest that double mutant mice fail to generate autoimmunity due to their decreased B cell cyclin D2 accumulation, and thus proliferation, in response to the elevated levels of IL-4 produced by mutant T cells.

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Mar 15, 2006·Immunology Letters·Jason J CoughlinJames C Stone

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Citations

Dec 31, 2015·Arthritis Research & Therapy·Marie-Laure GolinskiThierry Lequerré
Dec 23, 2008·Experimental Hematology·Stacey L StangJames C Stone
Jun 16, 2015·Genetic Testing and Molecular Biomarkers·Jun-Yan LiHao Lu
Mar 15, 2006·Immunology Letters·Jason J CoughlinJames C Stone
Jun 10, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Andrew FerrettiRobert A Barrington
Sep 3, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Amber BartlettRobert A Barrington
Oct 21, 2006·Biochemical Society Transactions·J C Stone
May 18, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Christopher SmithRobert A Barrington

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