CIS and TGF‐β regulatory pathways influence immunity to bacterial infection

Abstract Immunotherapy has revolutionized cancer therapy by reactivating tumour‐resident cytotoxic lymphocytes. More recently, immunotherapy has emerged to restore immunity against infectious agents, including bacterial infections. Immunotherapy primarily targets inhibitory pathways in T cells, however interest in other effector populations, such as natural killer (NK) cells, is growing. We have previously discovered that NK cell metabolism, proliferation and activation can be neutralized through the immunosuppressive transforming growth factor (TGF)‐β pathway by inducing plasticity of NK cells and differentiation into innate lymphoid cell (ILC)1‐like subsets. NK cells are also regulated through cytokine‐inducible SH2‐containing protein (CIS), which is induced by interleukin (IL)‐15 and is a potent intracellular checkpoint suppressing NK cell survival and function. Targeting these two distinct pathways to restore NK cell function has shown promise in cancer models, but their application in bacterial infection remains unknown. Here, we investigate whether enhancement of NK cell function can improve anti‐bacterial immunity, using Salmonella Typhimurium as a model. We identified conversion of NK cells to ILC1‐like for the first time in the context of bacterial infection, where TGF‐β signalling contributed to this plasticity. Future study should focus on identifying further drivers of ILC1 plasticity and its functional implication in bacterial infection model. We further describe that CIS‐deficient mice displayed enhanced pro‐inflammatory function and dramatically enhanced anti‐bacterial immunity. Inhibition of CIS may present as a viable therapeutic option to enhance immunity towards bacterial infection.