Producción CyT

IAS?USA/CROI Foundation - CD8 T-Cell Terminal Differentiation and Its Regulation by DHEA in HIV-TB Coinfection

Congreso

Autoría:

Guadalupe Suarez ; Matias Angerami ; Maria Vecchione ; SALOMON, HORACIO EDUARDO ; Maria Quiroga ; Omar Sued

Fecha:

2015

Editorial y Lugar de Edición:

CROI FOUNDATION

ISSN:

9780692369029

Resumen *

Background: Tuberculosis (TB) is the first cause of death in HIV+ patients. Mtb infection elicits CD8 T cell (CD8Tc) responses that contribute to control latent TB (LTB). We previously showed that Dehydroepiandrosterone (DHEA) in vitro reduces FoxP3 expression while raises Mtb-induced IFN-􀁡 release in HIV-TB patients. In this study we explored the anti-tubercular function and effector/memory phenotype of CD8Tc during HIV-TB co-infection and their modulation by DHEA. Methods: 47 HIV+ with active TB (HIV-TB), 12 HIV+/TST+ (HIV-LTB), 12 HIV+/TST- (HIV+) and 25 healthy (HD) individuals were studied. Memory subsets, determined by CD27 and CD45RA staining, and ex-vivo IFN-􀁡 production and CD107a/b staining in CD8Tc were assessed by flow cytometry. DHEA plasma levels were measured and the expression of transcription factors involved in effector/memory setting was evaluated by RT-PCR. Data was analyzed by using non-parametric tests. Results: Bulk CD8Tc in HIV+, HIV-LTB and HIV-TB patients showed different memory subset distribution compared to HD (p<0.05 by partial permutation test), with lower naïve (CD27+CD45RA+, TN) proportions in HIV-LTB and HIV-TB (p<0.05 by Kruskal-Wallis followed by Dunns -KWD-) and higher effector memory (CD27-CD45RA-, TEM, p<0.001 by KWD)and terminal effector (CD27-CD45RA+, TTE, p<0.05 by KWD) frequencies only in HIV-TB patients. Despite this increase, TTE cells from HIV-TB showed lower CD45RA levels (p<0.01 vs. HD by KWD) suggesting a not fully differentiated phenotype. These changes were not related to TB localization or BAAR status but HAART partially restored TN and TEM levels in CD8Tc from HIV-TB (p<0.05 by Wilcoxon matched-pairs signed rank test -Wmp-). Also, HIV-TB patients showed increased TEM and TTE frequencies in CD107a/b+ and IFN􀁡+ Mtb-specific CD8Tc respectively (p<0.05 vs. HD by KWD). DHEA plasma levels positively correlated with the % of TTE in bulk CD8Tc (Spearman r=0.47, p=0.027) and DHEA in vitro enhanced Mtb-specific CD8Tc degranulation (p<0.05 vs. Mtb by Wmp) and TTE CD107a/b+ proportions (p<0.05 vs. media by KWD) in HIV-TB. DHEA also raised Tbet expression and Tbet/EOMES ratio (p<0.01 vs. media by KWD) in Mtb-stimulated CD8+ cells. Conclusions: These data indicate that DHEA can induce terminal differentiation in CD8Tc during HIV-TB co-infection. To date, this is the first in-depth study of CD8Tc effector/memory phenotype in HIV-TB patients and its modulation by DHEA. We propose the use of DHEA as an adjunct therapy during Mtb infection in people living with HIV. Información suministrada por el agente en SIGEVA

Palabras Clave

HIV-TBDHEATERMINAL DIFFERENTIATIONCOINFECTION