The CD8+HLA-DR+ T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls

HIV-induced immune activation leads to expansion of a subset of human CD8+ T cells expressing HLA-DR antigens. Expansion of CD8+HLA-DR+ T cells can be also observed in non-HIV settings including several autoimmune diseases and aging. Although these cells are felt to represent immune exhaustion and/or to be anergic, their precise role in host defense has remained unclear. Here, we report that this subset of cells exhibits a restricted repertoire, shows evidence of multiple rounds of division, but lacks markers of recent TCR engagement. Detailed cell cycle analysis revealed that compared with their CD8+HLA-DR- counterpart, the CD8+HLA-DR+ T-cell pool contained an increased fraction of cells in S-phase with elevated levels of the G2/M regulators: cyclin A2, CDC25C, Cdc2 (CDK1), indicating that these cells are not truly anergic but rather experiencing proliferation in vivo. Together, these data support a hypothesis that antigen stimulation leads to the initial expansion of a CD8+ pool of cells in vivo that undergo further expansion independent of ongoing TCR engagement. No qualitative differences were noted between CD8+HLA-DR+ cells from HIV+ and HIV- donors, indicating that the generation of CD8+HLA-DR+ T cells is a part of normal immune regulation that is exaggerated in the setting of HIV-1 infection.