RESUMO
CD200R is a member of the Ig supergene family that is primarily expressed on myeloid cells. Recent in vivo studies have suggested that CD200R is an inhibitory receptor capable of regulating the activation threshold of inflammatory immune responses. Here we provide definitive evidence that CD200R is expressed on mouse and human mast cells and that engagement of CD200R by agonist Abs or ligand results in a potent inhibition of mast cell degranulation and cytokine secretion responses. CD200R-mediated inhibition of FcepsilonRI activation was observed both in vitro and in vivo and did not require the coligation of CD200R to FcepsilonRI. Unlike the majority of myeloid inhibitory receptors, CD200R does not contain a phosphatase recruiting inhibitory motif (ITIM); therefore, we conclude that CD200R represents a novel and potent inhibitory receptor that can be targeted in vivo to regulate mast cell-dependent pathologies.
Assuntos
Antígenos de Superfície/fisiologia , Mastócitos/imunologia , Mastócitos/metabolismo , Glicoproteínas de Membrana/fisiologia , Animais , Antígenos CD , Antígenos de Superfície/biossíntese , Antígenos de Superfície/imunologia , Antígenos de Superfície/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Degranulação Celular/imunologia , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Regulação para Baixo/imunologia , Sangue Fetal/citologia , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Humanos , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Orexina , Receptores de Superfície Celular , Receptores de IgE/antagonistas & inibidores , Receptores de IgE/fisiologia , Pele/citologia , Pele/imunologia , Pele/metabolismoRESUMO
Interleukin (IL)-23 is a heterodimeric cytokine composed of a unique p19 subunit, and a common p40 subunit shared with IL-12. IL-12 is important for the development of T helper (Th)1 cells that are essential for host defense and tumor suppression. In contrast, IL-23 does not promote the development of interferon-gamma-producing Th1 cells, but is one of the essential factors required for the expansion of a pathogenic CD4(+) T cell population, which is characterized by the production of IL-17, IL-17F, IL-6, and tumor necrosis factor. Gene expression analysis of IL-23-driven autoreactive T cells identified a unique expression pattern of proinflammatory cytokines and other novel factors, distinguishing them from IL-12-driven T cells. Using passive transfer studies, we confirm that these IL-23-dependent CD4(+) T cells are highly pathogenic and essential for the establishment of organ-specific inflammation associated with central nervous system autoimmunity.
