Myeloid derived suppressor cells (MDSC) from HIV-infected individuals are defective in innate immunity to Mycobacterium tuberculosis thus increasing the risk of tuberculosis

Abstract

Abstract Tuberculosis (TB) during HIV-infection can occur at any disease stage, even when CD4+ T cell number are reconstituted and virus replication suppressed. We previously showed that compared to HIV-uninfected, immune suppressive CD14+ MDSC are higher in HIV-infected individuals on combined antiretroviral therapy (cART) and with virus suppression. Here we examined if MDSC isolated from HIV-infected individuals are responsible for defective immunity to M tuberculosis (Mtb). PBMCs from HIV-infected individuals on cART and with viral suppression were isolated and CD14+HLA DRhi (DRhi) and HLA DR−/lo (MDSC) cell subsets were sorted by flow cytometry (FACS) and analyzed for the expression of TLR-2, -4 and IL-27R. FACS analysis showed that MDSC and DRhi subsets had comparable expression of surface TLR-2 (p=0.21) and TLR-4 (p=0.13); expression of IL-27R was high on MDSC (p=0.002). MDSC and DRhi subsets were infected with GFP expressing Mtb Erdman strain at MOI 5 in the presence of neutralizing IL-27 or isotype match control antibody. FACS analysis at 2-hrs post infection showed a higher expression of intracellular ROS in DRhi as compared to MDSC subsets (p= 0.05). Neutralization of IL-27 increased ROS expression of DRhi (p=0.005) but not MDSC subset (p=0.07). Furthermore, MDSC as compared to DRhi subset exhibited a higher intracellular replication of Mtb at day-5 post infection (p=0.01). Lastly, gene expression of intracellular MyD88 in MDSC as compared to DRhi subset was lower in response to Mtb (p=0.05). These findings suggest that MDSC in HIV-infected individuals inhibit protective immunological response to Mtb and increase the risk of TB disease in these individuals.