Date of Award
Doctor of Philosophy (PhD)
Natural killer (NK) cells are cytotoxic innate immune cells that provide protection from pathogens and tumors. To carry out these functions, NK cells must distinguish between healthy and unhealthy self-cells. Inability to recognize stressed cells would lead to a failure of NK-cell immunity whereas inability to identify healthy cells could lead to NK-cell autoimmunity. It remains unclear, however, how NK cells are able to distinguish healthy and unhealthy self-cells with a limited repertoire of germline-encoded receptors. The "missing-self" hypothesis proposes that NK cells identify stressed cells by their reduced expression of MHC class I (MHC-I) that is almost ubiquitously expressed as self. NK cells express inhibitory Ly49 receptors that bind to MHC-I and inhibit NK cells from killing healthy cells, and downregulation of MHC-I on stressed cells leads to loss of inhibition and killing by missing-self recognition. The importance of Ly49 receptors and MHC-I for maintaining NK-cell self-tolerance, however, has only been suggested by in vitro experiments and correlative in vivo experiments. Here we generated a mouse with a mutation in the immunoreceptor tyrosine-based inhibitory motif of Ly49A and another mouse with an allele of the gene for beta2-microglobulin containing loxP sites (B2m fl) to directly test the roles of Ly49s and MHC-I in NK cell self-tolerance in vivo. Loss of inhibitory signaling through a mutant Ly49 or global MHC-I downregulation induced changes in NK-cell responsiveness or inhibitory receptor expression that maintained NK-cell self-tolerance. In contrast, downregulation of MHC-I on CD4+ T cells, led to a subtle loss of CD4+ T cells, but NK cells remained tolerant to a substantial population of MHC-I-deficient CD4+ T cells without altering their responsiveness or receptor repertoire. In this setting, infection with murine cytomegalovirus or treatment with a toll-like receptor agonist induced NK cell-mediated rejection of MHC-I-deficient CD4+ T cells. These results show that loss of inhibitory signaling to NK cells in vivo can induce tolerance or rejection of missing-self in different contexts and that inflammation promotes missing-self reactivity.
Chair and Committee
Wayne M. Yokoyama
Paul M. Allen, Marco Colonna, Takeshi Egawa, Todd A. Fehniger,
Bern, Michael, "In Vivo Mechanisms of Natural Killer Cell Tolerance" (2020). Arts & Sciences Electronic Theses and Dissertations. 2167.