Implications of a ‘Third Signal’ in NK Cells

Innate and adaptive immune systems are evolutionarily divergent. Primary signaling in T and B cells depends on somatically rearranged clonotypic receptors. In contrast, NK cells use germline-encoded non-clonotypic receptors such as NCRs, NKG2D, and Ly49H. Proliferation and effector functions of T and B cells are dictated by unique peptide epitopes presented on MHC or soluble humoral antigens. However, in NK cells, the primary signals are mediated by self or viral proteins. Secondary signaling mediated by various cytokines is involved in metabolic reprogramming, proliferation, terminal maturation, or memory formation in both innate and adaptive lymphocytes. The family of common gamma (γc) cytokine receptors, including IL-2Rα/β/γ, IL-7Rα/γ, IL-15Rα/β/γ, and IL-21Rα/γ are the prime examples of these secondary signals. A distinct set of cytokine receptors mediate a ‘third’ set of signaling. These include IL-12Rβ1/β2, IL-18Rα/β, IL-23R, IL-27R (WSX-1/gp130), IL-35R (IL-12Rβ2/gp130), and IL-39R (IL-23Rα/gp130) that can prime, activate, and mediate effector functions in lymphocytes. The existence of the ‘third’ signal is known in both innate and adaptive lymphocytes. However, the necessity, context, and functional relevance of this ‘third signal’ in NK cells are elusive. Here, we define the current paradigm of the ‘third’ signal in NK cells and enumerate its clinical implications.