RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling.
J Immunol
; 175(11): 7179-84, 2005 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-16301621
ABSTRACT
The RasGRPs are a family of Ras activators that possess diacylglycerol-binding C1 domains. In T cells, RasGRP1 links TCR signaling to Ras. B cells coexpress RasGRP1 and RasGRP3. Using Rasgrp1 and Rasgrp3 single and double null mutant mice, we analyzed the role of these proteins in signaling to Ras and Erk in B cells. RasGRP1 and RasGRP3 both contribute to BCR-induced Ras activation, although RasGRP3 alone is responsible for maintaining basal Ras-GTP levels in unstimulated cells. Surprisingly, RasGRP-mediated Ras activation is not essential for B cell development because this process occurs normally in double-mutant mice. However, RasGRP-deficient mice do exhibit humoral defects. Loss of RasGRP3 led to isotype-specific deficiencies in Ab induction in immunized young mice. As reported previously, older Rasgrp1-/- mice develop splenomegaly and antinuclear Abs as a result of a T cell defect. We find that such mice have elevated serum Ig levels of several isotypes. In contrast, Rasgrp3-/- mice exhibit hypogammaglobulinemia and show no signs of splenomegaly or autoimmunity. Double-mutant mice exhibit intermediate serum Ab titers, albeit higher than wild-type mice. Remarkably, double-mutant mice exhibit no signs of autoimmunity or splenomegaly. B cell proliferation induced by BCR ligation with or without IL-4 was found to be RasGRP1- and RasGRP3-dependent. However, the RasGRPs are not required for B cell proliferation per se, because LPS-induced proliferation is unaffected in double-mutant mice.
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Base de dados:
MEDLINE
Assunto principal:
Linfócitos B
/
Receptores de Antígenos de Linfócitos B
/
Proteínas ras
/
Fatores de Troca do Nucleotídeo Guanina
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Proliferação de Células
/
Formação de Anticorpos
Limite:
Animals
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article