HIV-TB co-infection impairs CD8+ T-cell differentiation and function while dehydroepiandrosterone improves cytotoxic anti-tubercular immune responses

Abstract

Tuberculosis (TB) is the leading cause of death among HIV positive patients. The decreasing frequencies of terminal effector (TTE) CD8+T cells may increase reactivation risk in persons latently infected with Mycobacterium tuberculosis (Mtb). We have previously shown that dehydroepiandrosterone (DHEA) increases the protective anti-tubercular immune responses in HIV-TB patients. Here, we aimed to study Mtb-specific cytotoxicity, IFN-γ secretion, memory status of CD8+T cells, and their modulation by DHEA during HIV-TB coinfection. CD8+T cells from HIV-TB patients showed a more differentiated phenotype with diminished naïve (TN) and higher effector memory (TEM) and terminal effector (TTE) T-cell frequencies compared to healthy donors (HD) both in total and Mtb-specific CD8+T cells. Notably, CD8+T cells from HIV-TB patients displayed higher TTE CD45RAdim proportions with lower CD45RA expression levels, suggesting a not-fully differentiated phenotype. Also, PD-1 expression levels on CD8+T cells from HIV-TB patients increased although restricted to the CD27+ population. Interestingly, DHEA plasma levels positively correlated with TTE in CD8+ T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8+T cells from HIV-TB. Our data suggest that HIV-TB co-infection promotes a deficient CD8+ T-cell differentiation, whereas DHEA may contribute to improving anti-tubercular immunity by enhancing CD8+T-cell functions during HIV-TB co-infection