Abstract
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.
Highlights
Natural Killer (NK) cells protect hosts by eliminating pathogens and transformed malignant cells
The healthy cells, by virtue of expressing host MHC class I molecules on the cell surface are defined as ‘immunological self ’, which are recognized by inhibitory human killer cell immunoglobulin-like receptors (KIRs) or murine Ly49 receptors initiating negative signaling that trigger membrane-proximal phosphatases to block any activation effectively
NKG2D ligands are in chromosome 6, which are grouped into two families, MHC class I chain-related protein (MIC) and UL16-binding protein (ULBP)
Summary
Natural Killer (NK) cells protect hosts by eliminating pathogens and transformed malignant cells. Viral infections often lead to the expression of ligands that are typically absent on healthy cells [10] These stress-induced ligands serve as the ‘danger signals’ and interact with activating receptors on NK cells to overrule the negative signaling initiated by MHC class I molecules, the immunological ‘induced-self ’ [10]. Myeloid-derived cells (dendritic cells, macrophages, and neutrophils) secrete cytokines and chemokines, regulating NK cell effector functions. Activation through the receptors for Type I IFN-α/β, IL-12, IL-18, IL-21, IL-23, IL-27, IL-35, and IL-39 form a distinct set of signaling that constitutes a ‘third signal’. This distinct activation set largely depends on STATs and TRAFs as the conduits of signal transduction [14]. We describe the molecular mechanism and the clinical relevance of ‘primary’, ‘secondary’, and ‘third signal’ that independently operate on NK cells
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