RESUMO
Pulmonary eosinophilia induced in C57BL/6 mice after Cryptococcus neoformans infection is driven by CD4(+) Th2 cells. The immunological mechanisms that protect against eosinophilia are not fully understood. Interaction of OX40 (CD134) and its ligand, OX40L, has been implicated in T cell activation and cell migration. Unlike CD28, OX40 is only expressed on T cells 1-2 days after Ag activation. Manipulation of this pathway would therefore target recently activated T cells, leaving the naive repertoire unaffected. In this study, we show that engagement of OX40 by an OX40L:Ig fusion protein drives IFN-gamma production by CD4(+) T cells and reduces eosinophilia and C. neoformans burden in the lung. Using gene-depleted mice, we show that reduction of eosinophilia and pathogen burden requires IL-12 and/or IFN-gamma. C. neoformans infection itself only partially induces OX40L expression by APCs. Provision of exogenous OX40L reveals a critical role of this pathway in the prevention of C. neoformans-induced eosinophilia.
Assuntos
Adjuvantes Imunológicos/metabolismo , Cryptococcus neoformans/imunologia , Regulação para Baixo/imunologia , Ativação Linfocitária/imunologia , Eosinofilia Pulmonar/prevenção & controle , Receptores do Fator de Necrose Tumoral , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/microbiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/biossíntese , Adjuvantes Imunológicos/fisiologia , Animais , Antígenos de Diferenciação/administração & dosagem , Antígenos de Diferenciação/metabolismo , Brônquios/imunologia , Brônquios/metabolismo , Brônquios/microbiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Cryptococcus neoformans/crescimento & desenvolvimento , Eosinófilos/imunologia , Eosinófilos/patologia , Feminino , Injeções Intraperitoneais , Interferon gama/biossíntese , Interferon gama/deficiência , Interferon gama/genética , Interferon gama/fisiologia , Ligantes , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Glicoproteínas de Membrana/administração & dosagem , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligante OX40 , Eosinofilia Pulmonar/genética , Eosinofilia Pulmonar/microbiologia , Eosinofilia Pulmonar/patologia , Receptores OX40 , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/metabolismo , Subpopulações de Linfócitos T/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/administração & dosagem , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Fatores de Necrose TumoralRESUMO
The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20-55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host's tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.