Tuberculosis (TB) remains the most frequent cause of illness and death from an infectious agent, and its interaction with HIV has devastating effects. We determined plasma levels of dehydroepiandrosterone (DHEA), its circulating form DHEA-suphate (DHEA-s) and cortisol in different stages of M. tuberculosis infection, and explored their role on the Th1 and Treg populations during different scenarios of HIV-TB coinfection, including the immune reconstitution inflammatory syndrome (IRIS), a condition related to antiretroviral treatment. DHEA levels were diminished in HIV-TB and HIV-TB IRIS patients compared to healthy donors (HD), HIV+ individuals and HIV+ individuals with latent TB (HIV-LTB), whereas dehydroepiandrosterone sulfate (DHEA-s) levels were markedly diminished in HIV-TB IRIS individuals. HIV-TB and IRIS patients presented a cortisol/DHEA ratio significantly higher than HIV+, HIV-LTB and HD individuals. A positive correlation was observed between DHEA-s and CD4 count among HIV-TB individuals. Conversely, cortisol plasma level inversely correlated with CD4 count within HIV-TB individuals. M. tuberculosis-specific Th1 lymphocyte count was increased after culturing PBMC from HIV-TB individuals in presence of DHEA. We observed an inverse correlation between DHEA-s plasma level and Treg frequency in co-infected individuals, and CD4+FoxP3+ Treg frequency was increased in HIV-TB and IRIS patients compared to other groups. Strikingly, we observed a prominent CD4+CD25-FoxP3+ population across HIV-TB and HIV-TB IRIS patients, which frequency correlated with DHEA plasma level. Finally, DHEA treatment negatively regulated FoxP3 expression without altering Treg frequency in co-infected patients. These data suggest an enhancing role for DHEA in the immune response against M. tuberculosis during HIV-TB coinfection and IRIS.

Tuberculosis (TB) and HIV alter the immune system, and coinfected (HIV-TB) individuals usually present deregulations of T-lymphocytic immune response. We previously observed an increased frequency of “unconventional” CD4+CD25−FoxP3+ Treg (uTreg) population during HIV-TB disease. Therefore, we aimed to explore the phenotype and function of uTreg and conventional CD4+CD25+FoxP3+ Treg subsets (cTreg) in this context. We evaluated the expression of CD39, programmed cell death protein 1 (PD1), glucocorticoid-induced tumor necrosis factor receptor (GITR), and the effector/memory distribution by flow cytometry in cTreg and uTreg. Also, IL-10, TGF-β, IFN-γ production, and the suppressor capacity of uTregs were analyzed in cocultures with effector lymphocytes and compared with the effect of regulatory T cells (Tregs). We found diminished expression of CD39 and higher levels of PD1 on uTreg compared to cTreg in both HIV-TB and healthy donors (HD). In addition, uTreg and cTreg showed differences in maturation status in both HIV-TB and HD groups, due to the expansion of effector memory uTregs. Interestingly, both HIV-TB and HD showed a pronounced production of IFN-γ in uTreg population, though no significant differences were observed for IL-10 and TGF-β production between uTreg and cTreg. Moreover, IFN-γ+ cells were restricted to the CD39− uTreg population. Finally, when the suppressor capacity was evaluated, both uTreg and cTreg inhibited polyclonal T cell-proliferation and IFN-γ production in a similar extent. These findings suggest that uTregs, which are expanded during HIV-TB coinfection, exert regulatory functions in a similar way to cTregs despite an altered surface expression of Treg characteristic markers and differences in cytokine production.

Tuberculosis (TB) is the leading cause of death among HIV-positive patients. The decreasing frequencies of terminal effector (T TE ) 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 antitubercular 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 and higher effector memory and T TE T-cell frequencies compared to healthy donors both in total and Mtb-specific CD8 + T cells. Notably, CD8 + T cells from HIV-TB patients displayed higher Terminal Effector (T TE ) CD45RA dim 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 T TE in CD8 + T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8 + T cells from HIV-TB patients. Our data suggest that HIV-TB coinfection promotes a deficient CD8 + T-cell differentiation, whereas DHEA may contribute to improving antitubercular immunity by enhancing CD8 + T-cell functions during HIV-TB coinfection.Keywords: Coinfection r CD8 + T cells r Cell differentiation r DHEA r HIV r Tuberculosis Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Guadalupe V. Suarez e-mail: suarez_guadalupe@hotmail.com IntroductionNearly one-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), the etiologic agent of tuberculosis (TB). HIV coinfection is the main risk factor for progression C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2530 Guadalupe V. Suarez et al. Eur. J. Immunol. 2015. 45: 2529-2541 from latent to active TB disease, increasing the risk of latent TB (LTB) reactivation up to 20-fold [1]. It is well established that CD4 + T cells are critical for resistance to Mtb [2]. Mtb infection also elicits CD8 + T-cell responses, which are recruited to the lung during infection and found in the granulomas of infected people [3]. Although it is still unknown how CD8 + T cells may mediate protection against TB, it has been suggested that while CD4 + T cells are more important in controlling bacterial replication during the acute phase of infection, CD8 + T cells play a greater role during latency, possibly via immunesurveillance of cells with higher numbers of intracellular bacilli [4,5]. Besides cytokine secretion (IFN-γ and TNF-α), CD8 + T cells can induce T-cell-mediated cytotoxicity of infected cells, the major function of these cells [6]. Also, cytotoxic CD8 + T cells are able to directly kill intracell...

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