Interleukin-21 Regulates Natural Killer Cell Responses During & It;Mycobacterium Tuberculosis & It; Infection

Background. In the current study, we determined the effects of interleukin (IL)-21 on human natural killer (NK) cells and monocyte responses during Mycobacterium tuberculosis (Mtb) infection.Methods. We found that Mtb stimulated CD4(+) and NK T cells from healthy individuals with latent tuberculosis infection (LTBI+) are major sources of IL-21. CD4(+) cells from tuberculosis patients secreted less IL-21 than did CD4(+) cells from healthy LTBI+ individuals. Interleukin-21 had no direct effect on Mtb-stimulated monocytes.Results. Interleukin-21-activated NK cells produced interferon (IFN)-gamma, perforin, granzyme B, and granulysin; lysed Mtb-infected monocytes; and reduced Mtb growth. Interleukin-21-activated NK cells also enhanced IL-beta 1, IL-18, and CCL4/macrophage-inflammatory protein (MIP)-1 beta production and reduced IL-10 production by Mtb-stimulated monocytes. Recombinant IL-21 (1) inhibited Mtb growth, (2) enhanced IFN-gamma, IL-1 beta, IL-18, and MIP-1 beta, and (3) reduced IL-10 expression in the lungs of Mtb-infected Rag2 knockout mice.Conclusions. These findings suggest that activated T cells enhance NK cell responses to lyse Mtb-infected human monocytes and restrict Mtb growth in monocytes through IL-21 production. Interleukin-21-activated NK cells also enhance the immune response by augmenting IL-1 beta, IL-18, and MIP-1 beta production and reducing IL-10 production by monocytes in response to an intracellular pathogen.