IL-21-dependent expansion of memory-like NK cells enhances protective immune responses against Mycobacterium tuberculosis

Natural killer (NK) cells are traditionally considered as innate cells but recent studies suggest that NK cells can distinguish antigens, and that memory NK cells expand and protect against viral pathogens. Limited information is available about the mechanisms involved in memory-like NK cell expansion, and their role in bacterial infections and vaccine-induced protective immune responses. In the current study, using a mouse model of tuberculosis (TB) infection, we found that IFN-γ producing CD3-NKp46+CD27+KLRG1+ memory-like NK cells develop during Bacille Calmette-Guerin (BCG) vaccination, expand and provide protection against challenge with Mycobacterium tuberculosis (M. tb). Using antibodies, siRNA and gene-deleted mice, we found that expansion of memory-like NK cells depends on IL-21. NKp46+CD27+KLRG1+ NK cells expanded in healthy individuals with latent TB infection (LTBI) in IL-21 dependent fashion. Our study provides first evidence that memory-like NK cells survive long term, expansion depends on IL-21 and involved in vaccine induced protective immunity against a bacterial pathogen.