Superantigen activation of CD4+ and CD8+ T cells from HIV-infected subjects: role of costimulatory molecules and antigen-presenting cells (APC)

Abstract

Abstract T cell receptor (TCR) triggering via superantigens induces decreased proliferative responses and increased apoptosis in T cells from HIV-infected patients compared with controls. Our aim was to delineate the role of intrinsic T cell defects, of APC dysfunction and of cytokines and costimulatory signal dysregulation in the deficient responses of CD4+and CD8+ T cells from HIV+ subjects to the superantigen Staphylococcus enterotoxin A (SEA). Proliferation and IL-2Rα up-regulation on SEA-stimulated CD4+and CD8+T cells in whole blood were reduced in HIV+ subjects with CD4 counts < 500, compared with controls. Neither addition of IL-2, IL-12 or phorbol myristate acetate (PMA) nor neutralization of endogenous IL-10, tumour necrosis factor-alpha (TNF-α), TNF-β or transforming growth factor-beta (TGF-β) could restore the decreased activation by SEA. Possible intrinsic T cell defects were studied by presenting SEA on HLA-DR-transfected Chinese hamster ovary (CHO) cells, co-expressing LFA3 and/or CD80, to purified T cells. In this system CD8+T cells from most HIV+ patients were hyporesponsive with regard to IL-2 production, IL-2Rα up-regulation and proliferation, whereas clearly reduced responses were only shown in CD4+T cells from AIDS patients. Similarly, apoptosis was increased in CD8+T cells from all patients, but only in CD4+T cells from AIDS patients. During HIV infection, the responses to TCR triggering through SEA are deficient in both T cell subsets. The intrinsic defect appears earlier during disease progression in purified CD8+T than in CD4+T cells, it occurs in conjunction with both CD2 and CD28 costimulation, and it is correlated with increased levels of apoptosis.