CD4 on CD8⁺T cells directly enhances effector function and is a target for HIV infection

Abstract

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...

The CD4 molecule on CD8+T lymphocytes directly enhances the immune response to viral and cellular antigens

“…Our data suggest that, after cellular activation, a subset of CD8 ϩ T cells are induced to express CD4. We have previously determined that the newly expressed CD4 on human CD8 ϩ T cell modulates CTL, FasL, and IFN-␥ responses after ligation in vitro (9). Our current studies suggest that CD4 enhances the CD8 ϩ T cell response against viral and alloantigens in vivo through a similar mechanism.…”

“…In most cases, the rise in the percentage of CD8 ϩ CD4 ϩ cells appears to be a direct result of cellular activation, with these cells displaying a phenotype of activated or previously activated T cells. We and others have previously shown that costimulation of human CD8 ϩ T cells results in the de novo expression of CD4, consistent with the activated phenotype seen in vivo (9)(10)(11)(12)(13).…”

“…We have previously determined that CD4 can function as a chemotactic receptor on activated human CD8 ϩ T cells, allowing them to migrate in response to IL-16 (16). Furthermore, we have recently determined that CD4 can directly influence human CD8 T cell function in vitro (9). Ligation of CD4 on CD8 T cells sends a signal through the CD4-associated signaling molecule Lck, which results in up-regulation of Fas ligand (FasL) and IFN-␥, two molecules important in CD8 T cell function (9).…”

“…Furthermore, we have recently determined that CD4 can directly influence human CD8 T cell function in vitro (9). Ligation of CD4 on CD8 T cells sends a signal through the CD4-associated signaling molecule Lck, which results in up-regulation of Fas ligand (FasL) and IFN-␥, two molecules important in CD8 T cell function (9). Further, CD4 plays a direct role in CTL-mediated lysis of allogeneic B cell targets through interaction with MHC class II at the time of lytic activity.…”

Durable Human Memory T Cells Quantifiable by Cultured Enzyme-Linked Immunospot Assays Are Induced by Heterologous Prime Boost Immunization and Correlate with Protection against Malaria

“…that there is de novo expression of CD4 on CD8 cells after activation and in HIV-positive individuals, 0.7-3.3% of CD8 ϩ T cells are double positive and most of these cells are in the memory subset (28,29). A population of CD4 ϩ CD8 ϩ double positive T cells has been identified as effector memory cells, is shown to control viral replication in hepatitis C virus-infected individuals and is commonly found as memory populations in other species (30,31).…”