NOD2-deficient mice have impaired resistance to Mycobacterium tuberculosis infection through defective innate and adaptive immunity

J Immunol. 2008 Nov 15;181(10):7157-65. doi: 10.4049/jimmunol.181.10.7157.


NOD2/CARD15 mediates innate immune responses to mycobacterial infection. However, its role in the regulation of adaptive immunity has remained unknown. In this study, we examined host defense, T cell responses, and tissue pathology in two models of pulmonary mycobacterial infection, using wild-type and Nod2-deficient mice. During the early phase of aerosol infection with Mycobacterium tuberculosis, Nod2(-/-) mice had similar bacterial counts but reduced inflammatory response on histopathology at 4 and 8 wk postchallenge compared with wild-type animals. These findings were confirmed upon intratracheal infection of mice with attenuated Mycobacterium bovis bacillus Calmette-Guérin. Analysis of the lungs 4 wk after bacillus Calmette-Guérin infection demonstrated that Nod2(-/-) mice had decreased production of type 1 cytokines and reduced recruitment of CD8(+) and CD4(+) T cells. Ag-specific T cell responses in both the spleens and thoracic lymph nodes were diminished in Nod2(-/-) mice, indicating impaired adaptive antimycobacterial immunity. The immune regulatory role of NOD2 was not restricted to the lung since Nod2 disruption also led to reduced type 1 T cell activation following i.m. bacillus Calmette-Guérin infection. To determine the importance of diminished innate and adaptive immunity, we measured bacterial burden 6 mo after aerosol infection with M. tuberculosis and followed a second infected group for assessment of survival. Nod2(-/-) mice had a higher bacterial burden in the lungs 6 mo after infection and succumbed sooner than did wild-type controls. Taken together, these data indicate that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes
  • CD8-Positive T-Lymphocytes
  • Chemotaxis, Leukocyte
  • Cytokines / biosynthesis
  • Flow Cytometry
  • Immunity, Innate*
  • Lung / immunology
  • Lung / microbiology
  • Lung / pathology
  • Lymphocyte Activation / immunology
  • Macrophages, Alveolar / immunology
  • Macrophages, Alveolar / metabolism
  • Macrophages, Alveolar / microbiology
  • Mice
  • Microscopy, Confocal
  • Mycobacterium tuberculosis
  • Nod2 Signaling Adaptor Protein / deficiency*
  • Nod2 Signaling Adaptor Protein / immunology
  • Tuberculosis, Pulmonary / immunology*


  • Cytokines
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse