Glucocorticoid-Induced Tumor Necrosis Factor Receptor Family–Related Protein Triggering Enhances HIV-Specific CD4+ T Cell Cytokine Secretion and Protects HIV-Specific CD4+ T Cells from Apoptosis

摘要

Human immunodeficiency virus (HIV)–specific CD4⁺ T cell cytokine secretion is characteristically weak during HIV infection, in part because HIV-specific CD4⁺ T cells undergo massive apoptotic deletion. Glucocorticoid-induced tumor necrosis factor (TNF) receptor family–related (GITR) protein triggering enhances murine antigen-specific T cell cytokine secretion by protecting T cells from apoptosis. Therefore, we investigated the impact of GITR triggering on HIV-specific CD4⁺ T cell cytokine secretion and on apoptosis of HIV-specific CD4⁺ T cells. In HIV-infected subjects, CD4⁺ T cell surface expression of GITR was greater than that in uninfected control subjects, and phytohemagglutinin induction of additional GITR expression was impaired. However, antibody triggering of GITR significantly increased HIV-specific CD4⁺ T cell expression of TNF-α and interferon (IFN)–γ. The percentage increase in HIV-specific CD4⁺ T cell expression of TNF-α correlated directly with the absolute peripheral CD4⁺ T cell count. Furthermore, GITR triggering reduced the expression of intracellular activated caspase-3 in HIV-specific CD4⁺ T cells. Taken together, these data suggest that, despite abnormal GITR expression during HIV infection, GITR triggering enhances HIV-specific CD4⁺ T cell cytokine expression and protects HIV-specific CD4⁺ T cells from apoptosis.