NK1.1+ Cells and IL-22 Regulate Vaccine-Induced Protective Immunity against Challenge with Mycobacterium tuberculosis

Abstract

We previously found that human NK cells lyse Mycobacterium tuberculosis-infected monocytes and alveolar macrophages and upregulate CD8+ T cell responses. We also found that human NK cells produce IL-22, which inhibits intracellular growth of M. tuberculosis, and that NK cells lyse M. tuberculosis-expanded CD4+CD25+FOXP3+ T regulatory cells (Tregs). To determine the role of NK cells during the protective immune response to vaccination in vivo, we studied the NK cell and T cell responses in a mouse model of vaccination with bacillus Calmette-Guérin (BCG), followed by challenge with virulent M. tuberculosis H37Rv. BCG vaccination enhanced the number of IFN-γ–producing and IL-22–producing NK cells. Depletion of NK1.1+ cells at the time of BCG vaccination increased the number of immunosuppressive Tregs (CD4+CD25hi, 95% Foxp3+) after challenge with M. tuberculosis H37Rv, and NK1.1+ cells lysed expanded but not natural Tregs in BCG-vaccinated mice. Depletion of NK1.1+ cells at the time of BCG vaccination also increased the bacillary burden and reduced T cell responses after challenge with M. tuberculosis H37Rv. IL-22 at the time of vaccination reversed these effects and enhanced Ag-specific CD4+ cell responses in BCG-vaccinated mice after challenge with M. tuberculosis H37Rv. Our study provides evidence that NK1.1+ cells and IL-22 contribute to the efficacy of vaccination against microbial challenge.