Virulence-dependent induction of interleukin-10-producing-tolerogenic dendritic cells by Mycobacterium tuberculosis impedes optimal T helper type 1 proliferation.

Mycobacterium tuberculosis inhibits optimal T helper type 1 (Th1) responses during infection. However, the precise mechanisms by which virulent M. tuberculosis limits Th1 responses remain unclear. Here, we infected dendritic cells ( DCs) with the virulent M. tuberculosis strain H37Rv or the attenuated strain H37Ra to investigate the phenotypic and functional alterations in DCs and resultant T-cell responses. H37Rv-infected DCs suppressed Th1 responses more strongly than H37Ra-infected DCs. Interestingly, H37Rv, but not H37Ra, impaired DC surface molecule expression ( CD80, CD86 and MHC class II) due to prominent interleukin-10 ( IL-10) production while augmenting the expression of tolerogenic molecules including PD-L1, CD103, Tim-3 and indoleamine 2,3-dioxygenase on DCs in a multiplicity-of-infection (MOI) -dependent manner. These results indicate that virulent M. tuberculosis drives immature DCs toward a tolerogenic phenotype. Notably, the tolerogenic phenotype of H37Rv-infected DCs was blocked in DCs generated from IL-10^−/− mice or DCs treated with an IL-10-neutralizing monoclonal antibody, leading to restoration of Th1 polarization. These findings suggest that IL-10 induces a tolerogenic DC phenotype. Interestingly, p38 mitogen-activated protein kinase ( MAPK) activation predominantly mediates IL-10 production; hence, H37Rv tends to induce a tolerogenic DC phenotype through expression of tolerogenic molecules in the p38 MAPK- IL-10 axis. Therefore, suppressing the tolerogenic cascade in DCs is a novel strategy for stimulating optimal protective T-cell responses against M. tuberculosis infection. [ABSTRACT FROM AUTHOR]