Suppressing the suppressors: Regulating the inhibitory immune checkpoint in natural killer cells

Natural Killer (NK) cells play a crucial role in innate immunity, killing virally infected and cancerous cells. An unresolved question in NK cell biology is how NK cells rapidly discriminate between healthy and cancerous cells in a heterogeneous tissue environment, and the nature of the molecular mechanisms that regulate cytolytic and non-cytolytic synapses. The central negative regulator of NK cell activation is the protein tyrosine phosphatase, SHP-1, which dephosphorylates key signaling proteins, inhibiting NK cell function. Though we have partial insight regarding how SHP-1 mediates NK cell inhibition, the pathways by which SHP-1 is itself regulated throughout NK cell activation and inhibition are poorly understood. In addition, the role of the serine threonine kinase PKC Theta (PKCθ) in regulating human NK cell effector function has not been elucidated. Here, we identifies a novel role of PKCθ in human NK cell effector function, and elucidates a novel checkpoint in NK cell activity involving regulation of SHP-1, facilitating sustained NK cell activation, and tuning the NK cell activation threshold.