Pulmonary M. tuberculosis infection delays Th1 immunity via immunoadaptor DAP12-regulated IRAK-M and IL-10 expression in antigen-presenting cells

Mucosal Immunol. 2014 May;7(3):670-83. doi: 10.1038/mi.2013.86. Epub 2013 Oct 30.


Interaction of mycobacteria with the host leads to retarded expression of T helper cell type 1 (Th1) immunity in the lung. However, the immune mechanisms remain poorly understood. Using in vivo and in vitro models of Mycobacterium tuberculosis (M. tb) infection, we find the immunoadaptor DAP12 (DNAX-activating protein of 12 kDa) in antigen-presenting cells (APCs) to be critically involved in this process. Upon infection of APCs, DAP12 is required for IRAK-M (interleukin-1 receptor-associated kinase M) expression, which in turn induces interleukin-10 (IL-10) and an immune-suppressed phenotype of APCs, thus leading to suppressed Th1 cell activation. Lack of DAP12 reduces APC IL-10 production and increases their Th1 cell-activating capability, resulting in expedited Th1 responses and enhanced protection. On the other hand, adoptively transferred DAP12-competent APCs suppress Th1 cell activation within DAP12-deficient hosts, and blockade of IL-10 aborts the ability of DAP12-competent APCs to suppress Th1 activation. Our study identifies the DAP12/IRAK-M/IL-10 to be a novel molecular pathway in APCs exploited by mycobacterial pathogens, allowing infection a foothold in the lung.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antigen Presentation / immunology
  • Antigen-Presenting Cells / immunology*
  • Antigen-Presenting Cells / metabolism*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation
  • Inflammation Mediators / metabolism
  • Interleukin-1 Receptor-Associated Kinases / genetics
  • Interleukin-1 Receptor-Associated Kinases / metabolism*
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Lung / immunology
  • Lung / metabolism
  • Lung / microbiology
  • Lung / pathology
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mycobacterium tuberculosis / immunology*
  • NF-kappa B / metabolism
  • Signal Transduction
  • Th1 Cells / immunology*
  • Tuberculosis, Pulmonary / immunology*
  • Tuberculosis, Pulmonary / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Inflammation Mediators
  • NF-kappa B
  • Tyrobp protein, mouse
  • Interleukin-10
  • Interleukin-1 Receptor-Associated Kinases
  • Irak3 protein, mouse