Immune “checkpoint” inhibitor antibodies have revolutionized cancer therapy by reactivating tumour-killing immune cells. More recently, immune checkpoint therapy is emerging for its potential in restoring immunity against infectious agents. Checkpoint inhibitors primarily block inhibitory pathways in tumour-resident T cells, however interest in other effector populations, such as natural killer (NK) cells, is also growing. NK cells are key to cancer immunosurveillance, particularly in settings of metastasis, yet their potential for controlling bacterial infection is less clear. NK cells are dependent on the cytokine interleukin (IL)-15 for their survival, development, and function, but how this cytokine is regulated remains enigmatic. IL-15 signalling naturally employs negative feedback mechanisms to keep NK cell activation and function in check. One such mechanism is cytokine-inducible SH2-containing protein (CIS), which is induced by IL-15 and was described as a potent intracellular NK cell checkpoint that suppresses IL-15 receptor signalling. In addition, we have previously discovered that tumours can neutralize NK cell metabolism, proliferation, and activation by TGF-β immunosuppressive pathways by inducing plasticity of NK cells and differentiation into innate lymphoid cell (ILC)1-like subsets, which have a reduced capacity for tumour killing. Here, we investigate whether enhancement of NK cell function by targeting these regulatory mechanisms can improve anti-bacterial immunity, using Salmonella Typhimurium as a model. We identified for the first time NK cell to ILC1-like plasticity within a bacterial infection model, however the precise driver of plasticity in this model remains elusive. We further describe that CIS-deficient mice displayed enhanced pro-inflammatory function and dramatically enhanced anti-bacterial immunity. However, a CIS and TGF-β signalling-double-deficient NK cell mouse model did not synergize for increased resistance to infection.