RESUMO
Self-reactive T cells in the body are controlled by mechanisms of peripheral tolerance that limit their activation and induction of immune pathology. Our understanding of these mechanisms has been advanced by the use of tissue-specific promoters to express neo-self-antigens. Here, we present findings using the RIP-gp (rat insulin promoter-glycoprotein) transgenic mouse, which expresses the lymphocytic choriomeningitis virus glycoprotein (LCMV-gp) specifically in the pancreatic ß islet cells. T cells responsive to this antigen remain ignorant of the LCMV-gp expressed by the islets, and breaking tolerance is dependent upon the maturation status of antigen-presenting cells, the avidity of the T-cell receptor ligation, and the level of major histocompatibility complex expression in the pancreas. Furthermore, decreased activity of Casitas B-lineage lymphoma b, a negative regulator of T-cell receptor signaling, can allow recognition and destruction of the pancreatic islets. This review discusses the roles of these factors in the context of anti-tissue responses, both in the setting of autoimmunity and in anti-tumor immunity.
Assuntos
Autoantígenos/metabolismo , Doenças Autoimunes/imunologia , Glicoproteínas/metabolismo , Células Secretoras de Insulina/metabolismo , Neoplasias/imunologia , Proteínas do Envelope Viral/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Autoantígenos/genética , Autoantígenos/imunologia , Glicoproteínas/genética , Humanos , Insulina/genética , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Transgênicos , Especificidade de Órgãos , Regiões Promotoras Genéticas/genética , Tolerância a Antígenos Próprios , Transgenes/genética , Proteínas do Envelope Viral/genéticaRESUMO
Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors.