CD8+ T Cells Are Activated in an Antigen-Independent Manner in HIV-Infected Individuals

Abstract

Hyperactivation of T cells, particularly of CD8+ T cells, is a hallmark of chronic HIV 1 (HIV-1) infection. Little is known about the antigenic specificities and the mechanisms by which HIV-1 causes activation of CD8+ T cells during chronic infection. We report that CD8+ T cells were activated during in vivo HIV-1 replication irrespective of their Ag specificity. Cytokines present during untreated HIV-1 infection, most prominently IL-15, triggered proliferation and expression of activation markers in CD8+ T cells, but not CD4+ T cells, in the absence of TCR stimulation. Moreover, LPS or HIV-1–activated dendritic cells (DCs) stimulated CD8+ T cells in an IL-15–dependent but Ag-independent manner, and IL-15 expression was highly increased in DCs isolated from viremic HIV-1 patients, suggesting that CD8+ T cells are activated by inflammatory cytokines in untreated HIV-1 patients independent of Ag specificity. This finding contrasts with CD4+ T cells whose in vivo activation seems biased toward specificities for persistent Ags. These observations explain the higher abundance of activated CD8+ T cells compared with CD4+ T cells in untreated HIV-1 infection.

IL-15 promotes activation and expansion of CD8+ T cells in HIV-1 infection

“…We have previously reported a trend to increased production of supernatant IL-15 by LN histocultures of HIV-1-infected subjects (11). Increased IL15 mRNA was found in alveolar macrophages (34,35) and in blood myeloid dendritic cells of HIV-1-infected patients not receiving ART (35). Our study extends these earlier findings, placing them into context by providing strong evidence that IL-15 drives bystander memory CD8 + T cell expansion in HIV-1 infection, demonstrating high levels of IL-15 protein in LN sites of T cell maturation in untreated HIV-1-infected patients.…”

“…Although we could not find a correlation between IL-15 expression and plasma HIV-1 RNA levels, HIV-1 can induce IL-15 expression via TLR 7/8 ligation (49), and in chronic HIV-1 infection, increased gut mucosal barrier permeability permits systemic translocation of microbial products (50, 51) and their localization in lymphoid tissues (52) that also can induce expression of IL-15 (35). Further research is needed to understand better how CD8 + T numbers are maintained at high levels even after years of therapy as well as how persistent CD8 + T cell expansion during chronic HIV-1 infection is associated with increased morbidity and mortality (13, 21, 22).…”

CD8 T cell persistence in treated HIV infection

“…Some of this may be due the reactivation of latent pathogens such as Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) (16). Yet, CD8 T cells reactive to non-persistent pathogens such as influenza and adenovirus are also induced to expand, implying that CD8 T cell expansion occurs through antigen-independent mechanisms as well (17). In contrast, in the CD4 T cell compartment, expansion of cells reactive to persistent pathogens such as herpes viruses is demonstrable but CD4 T cell responses to non-persistent antigens are unaffected (18).…”

“…Microbial elements bind specific pathogen-associated molecular pattern receptors on antigen presenting cells (APCs) to induce pro-inflammatory cytokines; some of these can induce activation and proliferation of CD8 T cells in an antigen-independent manner (17). IFN-α can be induced by DCs primed with microbial products and in mice, IFN-a has been shown to induce memory CD8 T cell proliferation in an antigen-independent fashion (62, 63).…”

“…IL-15 is another cytokine induced by LPS-primed APCs (17). In mice, the absence of IL-15 led to slow attrition of memory CD8 T cells generated during acute LCMV infection (66), indicating that IL-15 is important in maintaining memory CD8 T cell persistence.…”