About this Research Topic
Natural killer (NK) cells are cytotoxic and cytokine-producing innate lymphocytes with important roles in antiviral and anti-tumor defense. In recent years, there is an increasing interest in their therapeutic use, as it has become possible to engineer them in a way that not only increases their cytolytic potential but also renders them specific for a given tumor type according to the antigen(s) expressed by the malignant cells. NK cell functions are governed by a balance between activating and inhibitory signaling transmitted by germline-encoded activating and inhibitory receptors, respectively. One important role of the inhibitory receptors such as the Ly49 receptors in mice and the Killer Immunoglobulin Receptors (KIR) in humans is to preserve tolerance through recognition of self Major Histocompatibility Complex (MHC) class I molecules. In mice, these inhibitory receptors are either specific for classical MHC class I molecules like H-2Kb or H-2Dd (Ly49 family) or for the non-classical MHC class Ib molecule Qa-1b that present peptides derived from the signal sequences of classical MHC class I molecules (CD94/NKG2A). In both cases, when these receptors bind to their ligand(s) on neighboring healthy cells, NK cell functions (cytotoxicity and cytokine production) are inhibited. In contrast, virally-infected and malignant cells may have absent or down-regulated MHC class I expression, signaling their damaged state to the NK cell and marking them for a cytotoxic fate. Equivalent inhibitory receptors in humans are the KIR receptors recognizing polymorphic classical Human Leukocyte Antigen (HLA) class I molecules and CD94/NKG2A (specific for the human Qa-1b equivalent HLA-E). Notably, these receptor-ligand interactions also tune the intrinsic functional potential of NK cells in a process termed as “education” or “licensing”. This potential paradoxically correlates with the strength of the inhibitory input during NK cell education. The more inhibition a cell receives during education, the higher is its functional potential. Conversely, NK cells that do not express self-specific inhibitory receptors and therefore lack the inhibitory input are hypo-responsive, a scenario that is exemplified in patients with MHC class I deficiencies. Despite differences in their cytotoxic capacities, both educated and uneducated NK cells exist within the vast NK repertoire and play important roles depending on the clinical environment. While educated NK cells may have higher intrinsic effector capacity making them superior at responding to target cells with genomic (e.g. leukemia cells following an HLA-mismatched stem cell transplantation) or induced (e.g. cytomegalovirus infection) loss of MHC class I, they are also susceptible to inhibition in inflammatory environments where MHC class I may be upregulated on the virally-infected or transformed cells. In the latter case, the uneducated NK cell may emerge as a vital surveyor of diseased cells.
Given the high genetic polymorphism in MHC binding receptors and their general stochastic expression, the process of education not only preserves self-tolerance but also contributes to the functional diversification of the NK cell repertoire within an individual and across populations. The scope of this Research Topic is (i) to review different models and hypotheses concerning the cellular and molecular mechanisms underlying NK cell education, and (ii) to discuss the relevance of education in the context of immunodeficiencies, viral infections, stem cell transplantation and cell therapy. We welcome the submission of Reviews, Mini-Reviews, Original Research articles, Hypotheses and Theory, Perspectives and Opinion articles to this collection.
Topic Editor Prof. Karl-Johan Malmberg holds equity in Fate Therapeutics. All other Topic Editors declare no competing interests with regards to the Research Topic subject.
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