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.
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- alpha and interferon (IFN)- gamma . The percentage increase in HIV-specific CD4(+) T cell expression of TNF- alpha 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.
Lahey
Timothy P
TP
Dartmouth Medical School, Lebanon, NH 03756, USA. Timothy.Lahey@Dartmouth.edu
Loisel
Suzanne D
SD
Wieland-Alter
Wendy
W
D000328:Adult; D017209:Apoptosis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D053148:Caspase 3 / Q000096:biosynthesis; D002462:Cell Membrane / Q000737:chemistry; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006678:HIV / Q000276:immunology*; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008875:Middle Aged; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000821:virology
D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human; D053148:Caspase 3