NK Cells Lyse T Regulatory Cells That Expand in Response to an Intracellular Pathogen

Abstract

We evaluated the capacity of NK cells to influence expansion of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in response to microbial Ags, using Mycobacterium tuberculosis as a model. We previously found that Tregs expand when CD4+ cells and monocytes are exposed to M. tuberculosis. Addition of NK cells that were activated by monokines (IL-12, IL-15, and IL-18) or by exposure to M. tuberculosis-stimulated monocytes reduced Treg expansion in response to M. tuberculosis. NK cell inhibition of Treg expansion was not mediated through IFN-γ. Activated NK cells lysed expanded, but not freshly isolated Tregs. Although monokines increased NK cell expression of the activating receptors NKp46, NKG2D, 2B4, CD16, and DNAM-1, only anti-NKG2D and anti-NKp46 inhibited NK cell lysis of expanded Tregs. Of five NKG2D ligands, only UL16-binding protein 1 (ULBP1) was up-regulated on M. tuberculosis-expanded Tregs, and anti-ULBP1 inhibited NK cell lysis of expanded Tregs. M. tuberculosis-stimulated monocytes activated NK cells to lyse expanded Tregs, and this was also inhibited by anti-NKG2D and anti-ULBP1, confirming the physiological relevance of this effect. Our study identifies a potential new role for NK cells in maintaining the delicate balance between the regulatory and effector arms of the immune response.

NK Cells Influence Both Innate and Adaptive Immune Responses after Mucosal Immunization with Antigen and Mucosal Adjuvant

“…NK cells mediate their effects through cellular cytotoxicity alongside the production of a range of cytokines and other immunoregulatory mediators (14)(15)(16)(17)(18)(19). Early resistance to intracellular pathogens, including M. tuberculosis, can be driven by IFN-g production and lysis of infected cells and through modulatory effects on T regulatory responses (20)(21)(22). Several studies have suggested that crosstalk between NK cells and APCs, such as dendritic cells (DCs) and macrophages (MFs), during the early phases of the immune response influences the type of adaptive immunity that follows (23)(24)(25).…”

Human tumor‐induced and naturally occurring Treg cells differentially affect NK cells activated by either IL‐2 or target cells

“…However, early in immune responses NK cells are further activated and recruited to tissue sites where they perform effector functions. It was recently reported that NK cells were capable of lysing pathogen-induced Treg cells, which expressed UL16-binding protein [40]. In contrast, it was demonstrated that Treg cells in a tumor microenvironment kill NK cells in a granzyme-B-dependent fashion [41].…”

NK cells and cancer: you can teach innate cells new tricks

“…Studies by Sentman and colleagues 166 have shown the in vitro efficacy of T cells expressing CARs based on NKG2D. These T cells are cytotoxic against tumour cells, but also against immunosuppressive myeloid cells and T Reg cells that transiently express NKG2DLs [167][168][169] . These 'improved' NKG2D CARs present advantages over the endogenous NKG2D receptors, because some of these CAR variants that do not associate with DAP10 (the signalling adaptor required for endogenous NKG2D receptor expression) are not down-modulated after exposure to the ligands 170 .…”