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

• Published in: Immunology Vol. 167; no. 1; pp. 54 - 63
• Main Authors: McCulloch, Timothy R., Rossi, Gustavo R., Schreuder, Jaring, Belz, Gabrielle T., Wells, Timothy J., Souza‐Fonseca‐Guimaraes, Fernando
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.09.2022
• Subjects: Bacteria; Bacterial diseases; Bacterial infections; Cancer; Cell activation; Cell differentiation; Cell proliferation; Cell survival; cellular plasticity; CIS; Cytokines; Cytotoxicity; Functional plasticity; Growth factors; Immunity; Immunotherapy; Infections; Inflammation; innate lymphoid cell 1; Interleukins; Lymphocytes; Lymphocytes T; Metabolism; Natural killer cells; Plastic properties; Plasticity; Recovery of function; Signal transduction; TGF‐βR signalling; Tumors; cellular plasticity; natural killer cells; CIS; innate lymphoid cell 1; TGF-βR signaling
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.13516

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. Natural killer cells are prevented from contributing towards immunity by suppressive pathways, including TGF‐β and CIS. Targeting these pathways has shown promise as a treatment in pre‐clinical cancer models, and may also be applicable for difficult to treat bacterial infections. This study explores the action of regulatory TGF‐β and CIS pathways on NK cell immunity during Salmonella Typhimurium infection.