IL-21 regulates NK cell responses during Mycobacterium tuberculosis infection. Padmaja Paidipally, Deepak Tripathi, Abhinav Van, Rajesh Kumar Radhakrishnan, Ramakrishna Vankayalapati1

Abstract

Abstract 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. We found that Mtb stimulated CD4+ and NKT 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. IL-21 had no direct effect on Mtb stimulated monocytes. IL-21 activated NK cells produced IFN-γ, perforin, granzyme B and granulysin; lysed Mtb infected monocytes; and reduced Mtb growth. IL-21 activated NK cells also enhanced IL-1β, IL-18, CCL4/MIP-1β production and reduced IL-10 production by Mtb stimulated monocytes. Recombinant IL-21 inhibited Mtb growth, enhanced IFN-γ, IL-1β, IL-18 and MIP-1β; and reduced IL-10 expression in the lungs of Mtb-infected Rag2 knockout (Rag2 KO) mice. 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. IL-21 activated NK cells also enhances the immune response by augmenting IL-1β, IL-18 and MIP-1β production and reducing IL-10 production by monocytes in response to an intracellular pathogen.