Skewing of the NK Cell Repertoire by MHC Class I via Quantitatively Controlled Enrichment and Contraction of Specific Ly49 Subsets

Abstract

A major task for the immune system is to secure powerful immune reactions while preserving self-tolerance. This process is particularly challenging for NK cells, for which tolerizing inhibitory receptors for self-MHC class I is both cross-reactive and expressed in an overlapping fashion between NK cells. We show in this study that during an education process, self-MHC class I molecules enrich for potentially useful and contract potentially dangerous NK cell subsets. These processes were quantitatively controlled by the expression level of the educating MHC class I allele, correlated with susceptibility to IL-15 and sensitivity to apoptosis in relevant NK cell subsets, and were linked to their functional education. Controlling the size of NK cell subsets with unique compositions of inhibitory receptors may represent one mechanism by which self-MHC class I molecules generate a population of tolerant NK cells optimally suited for efficient missing self-recognition.

A Genetic Defect in Mice That Impairs Missing Self Recognition Despite Evidence for Normal Maturation and MHC Class I–Dependent Education of NK Cells

“…Further studies of NK cell phenotypic markers did not support a defect in education, similar to b 2 m 2/2 mice, as an explanation for the phenotype of the IMSR mice. One hallmark of MHC class I-dependent education is skewing of the inhibitory MHC receptor repertoire (13,14). This skewing was even more accentuated in IMSR mice than in B6 mice, as compared to b 2 m 2/2 mice, indicating that host MHC molecules had indeed imposed an imprint on the repertoire.…”

“…To perform missing self recognition optimally, NK cells undergo an MHC class I-dependent education process. This process has two main influences: on the frequency of different NK subsets, as defined by their expression pattern of inhibitory receptors ("the NK repertoire") (13,14), and on the functional responsiveness status within each such cellular subset ("licensing") (15,16). The exact mechanisms underlying these MHC influences are not known.…”

Retuning of Mouse NK Cells after Interference with MHC Class I Sensing Adjusts Self-Tolerance but Preserves Anticancer Response

“…However, these have not been elucidated. Education has been associated with the lectin-like receptor KLRG1 (33,34), an adhesion molecule that acts as an inhibitory receptor on both NK and T cells and also as a marker for maturation or activation during a virus infection (41,42). The KLRG1 expression pattern has usually been considered as a downstream consequence of education rather than a mechanistic determinator.…”

“…There is a correlation between education and expression of killer cell lectin-like receptor G1 (KLRG1), with a higher frequency of KLRG1 þ cells among NK cells with receptors for self MHC class I (33,34). We therefore tested expression of KLRG1 on NK cells targeted by receptor blockade ( Fig.…”

Monosodium Urate Crystals Induce Upregulation of NK1.1-Dependent Killing by Macrophages and Support Tumor-Resident NK1.1+ Monocyte/Macrophage Populations in Antitumor Therapy

“…Regulation of NK receptor-mediated killer function has been linked to the expression of NK inhibitory and activating receptors (29)(30)(31), and Ly49 receptors are reported to be necessary for effective cancer immunosurveillance (32). In this study, upregulation of the inhibitory receptor Ly49A was observed over time, independent of macrophage stimulation or NK1.1 expression.…”