HIV-1 Tat affects the programming and functionality of human CD8+ T cells by modulating the expression of T-box transcription factors

OBJECTIVE:: HIV infection is characterized by several immune dysfunctions of both CD8 and CD4 T cells as hyperactivation, impairment of functionality and expansion of memory T cells. CD8 T-cell dysfunctions have been associated with increased expression of T-bet, Eomesdermin and pro-inflammatory cytokines, and with down-regulation of CD127. The HIV-1 trans-activator of transcription (Tat) protein, which is released by infected cells and detected in tissues of HIV-positive individuals, is known to contribute to the dysregulation of CD4 T cells; however, its effects on CD8 T cells have not been investigated. Thus, in this study, we sought to address whether Tat may affect CD8 T-cell functionality and programming. METHODS:: CD8 T cells were activated by T-cell receptor engagement in the presence or absence of Tat. Cytokine production, killing capacity, surface phenotype and expression of transcription factors important for T-cell programming were evaluated. RESULTS:: Tat favors the secretion of interleukin-2, interferon-γ and granzyme B in CD8 T cells. Behind this functional modulation we observed that Tat increases the expression of T-bet, Eomesdermin, Blimp-1, Bcl-6 and Bcl-2 in activated but not in unstimulated CD8 T lymphocytes. This effect is associated with the down-regulation of CD127 and the up-regulation of CD27. CONCLUSION:: Tat deeply alters the programming and functionality of CD8 T lymphocytes.