CD4+ and CD8+ T Cells Expressing FoxP3 in HIV-Infected Patients Are Phenotypically Distinct and Influenced by Disease Severity and Antiretroviral Therapy

Objectives: Forkhead box P3 (FoxP3) is critical for the development of CD4(+) regulatory T (Treg) cells and is a useful marker to identify this population. Recently, expression of FoxP3 was reported in human CD8(+) T cells from the blood of untreated HIV-infected individuals. We assessed whether FoxP3 expression in CD8(+) T cells is associated with suppressive potential and/or with HIV-associated immune activation. Methods: FoxP3(+)CD8(+) T cells in non-HIV donors and in untreated and treated HIV-infected patients were identified by flow cytometry, then examined for coexpression of other Treg cell-associated markers [cytotoxic T lymphocyte-associated antigen (CTLA)-4, GITR, and CD45RO], markers of activation [HLA-DRHI, Ki-67, and programmed death (PD)-1], and markers of senescence (CD57 without CD28). Results: Similar proportions of FoxP3-expressing CD4(+) and CD8(+) T cells coexpressed HLX-DRHI and Ki-67. However, compared with FoxP3(+)CD4(+) cells, FoxP3(+)CD8(+) cells expressed less CTLA-4, CD28, and CD45RO but more PD-1 and CD57. FoxP3-expressing CD4(+) and CD8(+) cells from untreated patients exhibited higher expression of HLA-DRHI, Ki-67, and PD-1 compared with non-HIV donors and treated patients. Conclusions: FoxP3(+)CD8(+) T cells are phenotypically distinct from FoxP3(+)CD4(+) and FoxP3(-)CD8(+) T cells. Expression of FoxP3 is associated with cellular activation in both CD4(+) and CD8(+) T cells.