RESUMO
The low-affinity receptor for IgG, FcgammaRIIb, negatively regulates B cell antigen receptor (BCR)-mediated proliferative signalling. FcgammaRIIb has been reported to mediate this inhibition by uncoupling the BCR from the RasMAPkinase pathway. We now show that FcgammaRIIb-mediated negative feedback inhibition also correlates with induction of an Erk-associated phosphatase activity that reflects the rapid association of Erk and the MAPkinase phosphatase, Pac-1, and dephosphorylation and inactivation of ErkMAPkinase. This mechanism of abrogating ongoing ErkMAPkinase signalling therefore provides a rationale for rapid immune-complex-mediated feedback inhibition of active antigen-driven B cell responses. In addition, FcgammaRIIb signalling also induces the recruitment and activation of the 3'-inositol phosphatase, PTEN, which by antagonising PI 3kinase activity and inhibiting BCR-coupling to the anti-apoptotic kinase, Akt, provides an additional mechanism for FcgammaRIIb-mediated negative regulation of BCR-coupling to ErkMAPkinase, cell survival and proliferation.
Assuntos
Linfócitos B/enzimologia , Regulação para Baixo/imunologia , Proteínas Tirosina Fosfatases/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Receptores de IgG/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Apoptose/genética , Apoptose/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Divisão Celular/genética , Divisão Celular/imunologia , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Cultivadas , Regulação para Baixo/genética , Fosfatase 2 de Especificidade Dupla , Retroalimentação Fisiológica/genética , Retroalimentação Fisiológica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , PTEN Fosfo-Hidrolase , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteína Fosfatase 2 , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Fosfatases/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de IgG/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteínas Supressoras de Tumor/genéticaRESUMO
ES-62 is a phosphorylcholine (PC)-containing glycoprotein secreted by filarial nematodes, parasites of vertebrates including humans. We have previously demonstrated that pre-exposure to this molecule in vitro interferes with subsequent B-cell receptor (BCR)-dependent activation of murine splenic B lymphocytes. To investigate the significance of this during filarial nematode infection, we now employ mice exposed to ES-62, at concentrations equivalent to those found for PC-containing molecules in the bloodstream of parasitized humans, via release from implanted osmotic pumps. Using this approach, we reveal that splenic and lymph node mononuclear cells, and also purified splenic B cells recovered from these mice have reduced ability ex vivo to proliferate in response to BCR ligation. The effect on BCR-induced proliferation was further investigated with respect to elucidating the mechanism of action of the parasite product and was shown to be associated with impaired signal transduction affecting the ErkMAPkinase pathway. Also, it was found that ES-62 did not act by promoting apoptosis or by priming for apoptosis following subsequent stimulation, but rather, appeared to render cells hyporesponsive to stimulation. ES-62 is thus shown for the first time to be a potent modulator of B lymphocyte function in vivo at a concentration relevant to natural filarial nematode infection. This finding considerably strengthens the idea that ES-62 plays a role in evasion of the immune response during parasitism.
