Costimulation of purified CD8 ؉ T lymphocytes induces de novo expression of CD4, suggesting a previously unrecognized function for this molecule in the immune response. Here, we report that the CD4 molecule plays a direct role in CD8 ؉ T cell function by modulating expression of IFN-␥ and Fas ligand, two important CD8 ؉ T cell effector molecules. CD4 expression also allows infection of CD8 cells by HIV, which results in down-regulation of the CD4 molecule and impairs the induction of IFN-␥, Fas ligand, and the cytotoxic responses of activated CD8 ؉ T cells. Thus, the CD4 molecule plays a direct role in CD8 T cell function, and infection of these cells by HIV provides an additional reservoir for the virus and also may contribute to the immunodeficiency seen in HIV disease. C D8 ϩ cytotoxic T lymphocytes (CTL) have a major role in antiviral immunity, directly killing virally infected cells and producing antiviral cytokines. Activation of these cells requires interaction of the T cell receptor complex with antigenic peptide and major histocompatibility complex (MHC) class I molecules on antigen-presenting cells (APCs) followed by a second costimulatory signal (1). After activation, there is a coordinated expression of various cell surface molecules, many of which play a direct role in cytotoxic activity. We and others have shown that costimulation of CD8 ϩ T cells from the peripheral blood results in the de novo expression of CD4, a molecule previously thought to be absent on this cell type at this stage of development (2-5). These CD8 ϩ CD4 ϩ cells express higher levels of activation molecules than do costimulated CD8 ϩ T cells lacking CD4 expression (2, 6). CD8 ϩ CD4 ϩ T cells constitute Ϸ3-5% of the human peripheral blood lymphocyte pool (7-10). Certain conditions seem to influence CD8 ϩ CD4 ϩ cell levels in humans, including infection with HIV (11), human T lymphotrophic virus-1 (12), Epstein-Barr virus (8), human herpesvirus 6 (13), and aging (10). CD8 ϩ CD4 ϩ cells also have been observed in monkeys (14-17), and in mice, rats, swine, and chickens (reviewed in ref. 18). In mice, CD8 ϩ CD4 ϩ cell levels increased after inoculation with reovirus or recombinant adenovirus (19,20). In each species, the CD8 ϩ CD4 ϩ populations usually displayed the phenotype of activated or previously activated T cells and, in the studies that assessed the composition of the CD8 dimer, were predominantly CD8␣ (versus CD8␣␣) cells (11,15,19). The presence of CD8 ϩ CD4 ϩ cells in normal individuals and the increased representation of these cells in individuals with disease or increased antigenic stimulation suggest a role for this cell type in immunity.The CD4 molecule has an important role in CD4 ϩ T helper (Th) cell development and response to antigen, including functioning as an adhesion molecule, regulating cellular activation and gene expression, and serving as a chemotactic receptor (21-23). Its role as the primary receptor for HIV is well known (24,25). The cytoplasmic tail of the CD4 molecule on Th cells is associated with t...
