Cycling Memory CD4⁺T Cells in HIV Disease Have a Diverse T Cell Receptor Repertoire and a Phenotype Consistent with Bystander Activation

Abstract

The mechanisms of increased memory CD4؉ T cell cycling in HIV disease are incompletely understood but have been linked to antigen stimulation, homeostatic signals, or exposure to microbial products and the inflammatory cytokines that they induce. We examined the phenotype and V␤ family distribution in cycling memory CD4 ؉ T cells among 52 healthy and 59 HIV-positive (HIV ؉ ) donors. Cycling memory CD4 ؉ T cells were proportionally more frequent in subjects with HIV infection than in controls, more often expressed CD38 and PD-1, and less frequently expressed OX40 and intracellular CD40L. OX40 expression on memory CD4؉ T cells was induced in vitro by anti-CD3, interleukin-2 (IL-2), IL-7, or IL-15 but not by Toll-like receptor ligands. In HIV ؉ donors, memory CD4 ؉ T cell cycling was directly related to plasma lipopolysaccharide (LPS) levels, to plasma HIV RNA levels, and to memory CD8 ؉ T cell cycling and was inversely related to peripheral blood CD4 ؉ T cell counts but not to the levels of IL-2, IL-7, or IL-15, while in HIV-negative donors, memory CD4 ؉ T cell cycling was related to IL-7 levels and negatively related to the plasma levels of LPS. In both controls and HIV ؉ donors, cycling memory CD4 ؉ T cells had a broad distribution of V␤ families comparable to that of noncycling cells. Increased memory CD4؉ T cell cycling in HIV disease is reflective of generalized immune activation and not driven primarily by cognate peptide stimulation or exposure to common gamma-chain cytokines. This cycling may be a consequence of exposure to microbial products, to plasma viremia, or, otherwise, to proinflammatory cytokines. IMPORTANCE This work provides evidence that the increased memory CD4؉ T cell cycling in HIV infection is not a result of cognate peptide recognition but, rather, is more likely related to the inflammatory environment of HIV infection.

Drug Use is Associated with Anti-CD4 IgG-mediated CD4+ T Cell Death and Poor CD4+ T Cell Recovery in Viral-suppressive HIV-infected Individuals Under Antiretroviral Therapy

“…Illicit drugs have been shown to associate with increased systemic inflammation [59, 60], which may result from cellular activation and oxidative stress [61, 62], and induction of gut microbial translocation [21, 22, 63, 64]. Studies from our group and others indicate that HIV infection is associated with a permeable gut, increased microbial translocation, and increased CD4+ T cell apoptosis and inflammation [11, 65-67]. Moreover, HIV Tat protein and gp120 directly reduce tight junction expression on epithelial cells in vitro [68, 69].…”

Inflammation Perturbs the IL-7 Axis, Promoting Senescence and Exhaustion that Broadly Characterize Immune Failure in Treated HIV Infection

“…Also, the lack of correlation between plasma IL-7 levels and T cell cycling in immune failure patients suggests that other factors may be driving T cell cycling in immune failure and are masking any relationship among IL-7 levels, T cell cycling and CD127 expression. In the setting of immune failure, cycling of memory CD4 T cells has the characteristics of broad bystander activation [45] and may be driven at least in part by exposure to IL-1β [18] and other inflammatory mediators such as IL-2 and IL-15, common gamma receptor cytokines whose expression is also elevated in lymphoid tissues [46]. Moreover, our new data demonstrating an inverse correlation between plasma levels of IL-6, LPS, and IP-10 with CD127 expression on CD8 T cells in immune failure suggests that the IL-7 axis is impaired in this inflammatory environment.…”

Soluble CD40-ligand (sCD40L, sCD154) plays an immunosuppressive role via regulatory T cell expansion in HIV infection

“…It was not surprising that sCD40L was elevated in ART-naive subjects with low CD4 T cell counts, as CD40L is expressed on activated T cells, which are the main targets for HIV infection [15,41]. Furthermore, it has been shown recently that the cell cycling CD4 memory T cells in chronically HIV-infected patients contains lower intracellular CD40L compared to healthy subjects [45]. Surprisingly, however, in the study by Sipsas et al, despite the higher plasma sCD40L levels evaluated in 77 patients with a mean CD4 T cell count of 335 ± 248 cells/μl compared to healthy subjects, the correlation between CD4 T cell count and plasma sCD40L was seen only for patients having CD4 T cell count <130 cells/μl, and they observed an unexpected positive correlation between CD4 count and sCD40L [14].…”