HIV myeloid derived suppressor cells (MDSC) are defective in innate immunity to Mycobacterium bovis BCG

Abstract

Abstract Disseminated BCG disease and reduced BCG-specific immunity in HIV infected individuals is often fatal in HIV/TB endemic regions. We previously showed that the immune suppressive CD14+ MDSC expand during in vitro or in vivo HIV-infection. Here we examined the factors responsible for defective anti-BCG immunity associated with HIV MDSC. PBMCs from HIV-uninfected healthy donors were cultured with inactivated HIVBaL. After 5 days CD14+HLA DRhi (DRhi) and HLA DR−/lo (MDSC) cell subsets were sorted by flow cytometry (FACS) and infected with BCG at MOI 5 with or without 25OH or 1,25OH vitamin D (vitD). When infected with BCG, DRhi compared to MDSC produced less IL-10 (p=0.04), and more TNF-α (p=0.02) and IL-1β (p=0.05). FACS analysis showed that MDSC compared to DRhi expressed comparable levels of nVDR (p=0.01), but low levels of CYP27B1 (p=0.003) and cathelicidin (p=0.01). The expression of CD86 on MDSC compared to DRhi in response to BCG was low (p=0.02), and remained low when MDSC were cultured in the presence of 25 OH (p=0.03). The expression of CD86 on BCG infected MDSC was comparable to that of BCG infected DRhi only when cultured in the presence of 1,25OH (p=0.07). Similarly, expression of HLA DR on MDSC compared to DRhi in response to BCG was low (p=0.04) and continued to be low in presence of 25OH (p=0.001). The expression of HLA DR on BCG infected MDSC was comparable to BCG infected DRhi only in the presence of 1,25OH (p=0.43). Finally, intracellular replication of BCG in MDSC isolated from HIV-infected individuals was higher compared to replication in DRhi cells (p=0.02). These findings suggest that the impaired killing of BCG by HIV MDSC is due to their defective vitD-cathelicidin mediated innate anti-mycobacterial activity