RESUMO
Glucocorticoid-induced tumor necrosis factor receptor (TNFR) (GITR) family-related gene is a member of the TNFR super family. GITR works as one of the immunoregulatory molecule on CD4+ regulatory T cells and has an important role on cell survival or cell death in CD4+ T cells. Little is known about the expression of GITR on human CD8+ T cells on antigen-specific and non-specific activation. Here, we report that expression of GITR on human CD8+ T cells on T-cell receptor (TCR) (anti-CD3)-mediated stimulation is dependent on the JNK pathway. The activation of CD8+ T cells was measured by the expression of IL-2 receptor-α (CD25), GITR and by IFN-γ production upon re-stimulation with anti-CD3 antibody. We studied the signaling pathway of such inducible expression of GITR on CD8+ T cells. We found that a known JNK-specific inhibitor, SP600125, significantly down-regulates GITR expression on anti-CD3 antibody-mediated activated CD8+ T cells by limiting JNK phosphorylation. Subsequently, after stimulation of the CD8+ cells, we tested for the production of IFN-γ by the activated cells following restimulation with the same stimulus. It appears that the expression of GITR on activated human CD8+ T cells might also be regulated through the JNK pathway when the activation is through TCR stimulation. Therefore, GITR serves as an activation marker on activated CD8+ cells and interference with JNK phosphorylation, partially or completely, by varying the doses of SP600125 might have implications in CD8+ cytotoxic T cell response in translational research.
Assuntos
Linfócitos T CD8-Positivos , Morte Celular/genética , Sobrevivência Celular/genética , Genes Codificadores dos Receptores de Linfócitos T/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Fosforilação/genéticaRESUMO
Gene analysis of tumor associated antigens revealed that tumor antigens are all normal gene product. Inducing tumor reactive cytotoxic T lymphocytes (CT) in the patients is same as inducing autoimmunity in the patients. Immunosuppressive cytokine interleukin-10 (IL-10) plays an important role in maintaining homeostasis or tolerance. To break the tumor tolerance, blocking and IL-10 secretion or intervention in the pathways of IL-10 gene activation is indeed important.