The role of RasGRPs in regulation of lymphocyte proliferation.
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.
Coughlin
Jason J
JJ
Department of Biochemistry, University of Alberta, Edmonton, Alta., Canada T6G 2H7.
Stang
Stacey L
SL
Dower
Nancy A
NA
Stone
James C
JC
D000818:Animals; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D066298:In Vitro Techniques; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction
D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D015847:Interleukin-4