Abstract
Expression of non-rearranged HLA class I-binding receptors characterizes human and mouse NK cells. The postulation of the missing-self hypothesis some 30 years ago triggered the subsequent search and discovery of inhibitory MHC-receptors, both in humans and mice. These receptors have two functions: (i) to control the threshold for NK cell activation, a process termed “licensing” or “education,” and (ii) to inhibit NK cell activation during interactions with healthy HLA class I-expressing cells. The discovery of activating forms of KIRs (aKIR) challenged the concept of NK cell tolerance in steady state, as well as during immune challenge: what is the biological role of the activating KIR, in particular when NK cells express aKIRs in the absence of inhibitory receptors? Recently it was shown that aKIRs also participate in the education of NK cells. However, instead of lowering the threshold of activation like iKIRs, the expression of aKIRs has the opposite effect, i.e., rendering NK cells hyporesponsive. These findings may have consequences during NK cell response to viral infection, in cancer development, and in the initial stages of pregnancy. Here we review the current knowledge of activating KIRs, including the biological concept of aKIR-dependent NK cell education, and their impact in health and disease.
Highlights
The history of non-rearranged MHC class I-binding receptors has been a passionate story for three decades
Other reports have suggested an HLA-Bw4-independent effect of KIR3DS1 in HIV-infected individuals, at least when measuring CD8 T cell activation, which is strongly associated with HIV disease progression [75]
One possible explanation, which is still compatible with activating forms of KIRs (aKIR)-mediated education, is that an unknown non-HLA class I ligand is expressed by leukemic blasts, and as such provides a mechanism by which KIR2DS1+ NK cells could recognize the leukemia blasts, but only if the donor-derived KIR2DS1+ NK cells are not rendered tolerant by the donors or recipient’s HLA-C2
Summary
The history of non-rearranged MHC class I-binding receptors has been a passionate story for three decades. The large degree of linkage disequilibrium between different KIR genes, e.g., KIR2DL2 and KIR2DS2, and KIR2DS1 and KIR3DS1, makes it hard to pinpoint a specific KIR/HLA class I interaction at the genetic level, as responsible for protection or susceptibility to a given infection. It is noteworthy that very little is known about co-expression of other activating and inhibitory KIRs and other HLA class I-binding receptors (e.g., NKG2A, NKG2C, and LIR-1) on KIR3DS1+ NK cells, both in healthy and in HIV-infected individuals.
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