RESUMEN
The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus-derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70-dependent Th1 priming, while leaving the IL-12-dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN-γ-secreting CD4(+) T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27-dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses.
Asunto(s)
Ligando CD27/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Timo/inmunología , Timo/metabolismo , Animales , Ligando CD27/genética , Células Dendríticas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/genética , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
The parasite Trypanosoma brucei possesses a large family of transmembrane receptor-like adenylate cyclases. Activation of these enzymes requires the dimerization of the catalytic domain and typically occurs under stress. Using a dominant-negative strategy, we found that reducing adenylate cyclase activity by about 50% allowed trypanosome growth but reduced the parasite's ability to control the early innate immune defense of the host. Specifically, activation of trypanosome adenylate cyclase resulting from parasite phagocytosis by liver myeloid cells inhibited the synthesis of the trypanosome-controlling cytokine tumor necrosis factor-α through activation of protein kinase A in these cells. Thus, adenylate cyclase activity of lyzed trypanosomes favors early host colonization by live parasites. The role of adenylate cyclases at the host-parasite interface could explain the expansion and polymorphism of this gene family.
Asunto(s)
Adenilil Ciclasas/metabolismo , Inmunidad Innata , Proteínas Protozoarias/metabolismo , Trypanosoma brucei brucei/enzimología , Trypanosoma brucei brucei/inmunología , Tripanosomiasis Africana/inmunología , Adenilil Ciclasas/química , Adenilil Ciclasas/genética , Animales , Dominio Catalítico , Línea Celular , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Activación Enzimática , Interacciones Huésped-Parásitos , Hígado/citología , Ratones , Ratones Endogámicos C57BL , Mutagénesis Sitio-Dirigida , Células Mieloides/inmunología , Parasitemia , Fagocitosis , Proteínas Protozoarias/química , Proteínas Protozoarias/genética , Proteínas Recombinantes de Fusión/metabolismo , Trypanosoma brucei brucei/crecimiento & desarrollo , Tripanosomiasis Africana/metabolismo , Tripanosomiasis Africana/parasitología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/sangreRESUMEN
The CD70/CD27 axis has gained increasing interest among the immunologists, because of its capacity to regulate immunity versus tolerance. Recent studies clearly show that expression of CD70 may prevent tolerance induced by antigen presentation in the steady-state, i.e., by nonactivated DCs. In addition, CD27 signaling appears critical for T cell expansion and survival and therefore, induction of long-term memory. It contributes to germinal center formation, B cell activation, and production of neutralizing antibodies but can also be subverted by viruses, in particular, during chronic infections. The potential role of the CD27/CD70 pathway in the course of inflammatory diseases, as in EAE, arthritis, and inflammatory bowel disease models, suggests that CD70 may be a target for immune intervention. Conversely, the potency of costimulation through CD27 suggests that the CD27/CD70 axis could be exploited for the design of anti-cancer vaccines.