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.
Bibliographical noteFunding Information:
This research was supported by the Basic Science Research Programme through the National Research Foundation of Korea (NRF) and funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1A2A1A05005263). HK and WSK designed and performed the experiments, analysed data, and wrote the manuscript. WSK and KWK performed research and contributed to the interpretation of the results. WSK and HK contributed to the discussion of the results and to writing the paper. SJS initiated the idea, supervised the team, designed the experiments, and critically revised the manuscript. All authors read and approved the final version of the manuscript.
All Science Journal Classification (ASJC) codes
- Immunology and Allergy