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

 Hongmin Kim  ;  Kee Woong Kwon  ;  Woo Sik Kim  ;  Sung Jae Shin 
 IMMUNOLOGY, Vol.151(2) : 177-190, 2017 
Journal Title
Issue Date
Animals ; Cell Proliferation ; Dendritic Cells/immunology* ; Dendritic Cells/metabolism ; Interleukin-10/biosynthesis* ; Interleukin-10/deficiency ; Interleukin-10/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mycobacterium tuberculosis/immunology* ; Th1 Cells/cytology* ; Th1 Cells/immunology* ; Virulence/immunology
Th1-type T-cell proliferation ; interleukin-10 ; p38 mitogen-activated protein kinase ; tolerogenic dendritic cells ; virulence
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.
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1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Shin, Sung Jae(신성재) ORCID logo https://orcid.org/0000-0003-0854-4582
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