The NKG2D receptor and its cognate ligands represent a fascinating immune recognition system, essential to the activation of innate and adaptive effector cells. It is a potent axis for the detection of danger recognized as MHC I-like self-molecules induced under stress conditions or during rapid proliferation. As such it complements the recognition of non-self-antigens presented by classic MHC molecules, ensuring an early and efficient elimination of threats. The strength of the NKG2D pathway relies on its capacity to: (i) activate several immune effector cells due to the wide expression of the NKG2D receptor on lymphocytes, and (ii) distinguish diverse types of stress via multiple ligands displaying distinct affinities and levels of regulation.

The central dogma states that NKG2D engagement initiates or strengthens immune responses against infected and tumor cells by means of cytokine and chemokine secretion and direct cytotoxic activity. However, recently we have started to appreciate the multifaceted involvement of this pathway in immunity. Several studies have revealed the ability of NK cells to shape immune responses in pathologic contexts by directly eliminating immune cells presenting NKG2D ligands. Other reports implicate NKG2D as an intrinsic regulator of NK cell and B cell development at steady state. Regarding NKG2D ligands, their expression in space and time is not fully understood. The type of ligand (membrane bound versus soluble), the amount of ligand expressed, and the cell types displaying ligands (tumor vs. normal tissue vs. stroma vs. immune cells) are likely to differentially impact on disease progression. Importantly, NKG2D ligand expression in healthy tissues is no longer anecdotal and it has become clear that NKG2D can contribute to the development of autoimmunity. Studies using pre-clinical models of disease have been critical in highlighting the paradoxical outcome of NKG2D/NKG2D-ligand engagement on disease progression (protective versus detrimental), including in cancer.

While the NKG2D receptor-ligand axis is recognized as an attractive target for immunotherapy against cancer and inflammatory disorders - more information is needed to optimally design and tailor strategies that either boost or block this peculiar pathway. This Research Topic will highlight recent advances on NKG2D and its ligands. We welcome the submission of Original Research articles focused on physiologic and pathologic settings, as well as Review and Opinion articles discussing the scope of NKG2D function based on human and mouse studies.

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