Defective IL-17 production is associated with reduced IL-1β levels in response to Mycobacterium tuberculosis in HIV+ children with latent tuberculosis infection.

INTRODUCTION: Children with latent tuberculosis (LTBI) infection are more susceptible to Mycobacterium tuberculosis (Mtb) disease than adults with LTBI. HIV infection in children significantly enhances the development of LTBI into active TB due to the immature immune system. However, information about the immune responses to Mtb in HIV+ children with LTBI is limited. METHODS: In this study, we compared the immune cell phenotypes of freshly isolated PBMCs as well as Mtb antigen specific cytokine and chemokine production in HIV-LTBI+ and HIV+LTBI+ children. We also identified the factors responsible for reduced IL-1β production by PBMCs from HIV+LTBI+ children. RESULTS: We found that compared to HIV-LTBI+ (healthy LTBI+) children, HIV+ children with LTBI have significantly fewer exhausted (LAG3+) NK cells and specific CD8+ cell subsets in freshly isolated PBMCs. We also found that in response to Mtb antigens, PBMCs from HIV+LTBI+ children produced less IL-1β, IL-17, IFN-γ and MCP-1 than PBMCs from HIV-LTBI+ children. Recombinant IL-17 significantly increased the production of IL-1β, MCP-1 and MIP-1α; increased the expansion of CD4+CD45RO+CCR7+CD62L+ T cells; and significantly decreased the number of CD3-CD56+CD158b (KIR2DL) expressing NK cells by CFP-10 and ESAT-6 stimulated PBMCs from HIV+LTBI+ children. DISCUSSION: We demonstrated that defective IL-17 production is associated with decreased secretion of the protective cytokines IL-1β, MCP-1 and MIP-1α in HIV+LTBI+ children. These findings highlight the need to investigate IL-17 mediated mechanisms to develop interventions for children with concurrent HIV and latent tuberculosis.