This is a revised competing continuation application that proposes to study the development of natural killer (NK) cells which are important constituents of the early host innate immune response to tumors and infections. They possess potent capacities to kill cells and secrete pro-inflammatory cytokines that must be controlled in order to prevent inadvertent tissue destruction, i.e., NK cells must display tolerance to self. In the prior funding period, the applicant's laboratory made several important contributions. The most important is related to how NK cells acquire self-tolerance. They showed that NK cells acquire the functional capacity to be triggered through their activation receptors to kill and produce cytokines. This process, termed """"""""licensing,"""""""" is mediated by Ly49 receptors on NK cells that recognize self-major histocompatibility complex (MHC) class I molecules. Ironically these receptors were originally identified as inhibitory receptors in NK cell effector responses. There are thus two types of self-tolerant NK cells, those that are licensed and inhibited by self-MHC through the same Ly49 receptors that conferred licensing and unlicensed NK cells that are tolerant because they are not functionally competent. However, unlicensed NK cells can derive enhanced function when pre-activated by other stimuli to bypass MHC-dependent licensing. Herein, the applicant proposes to study licensing in greater detail.
The specific aims of the proposal are to study: 1) Ly49 specificities for MHC alleles in licensing;2) MHC class I epitope recognized by Ly49 in licensing;3) Signal strength in licensing;and 4) Bypassing MHC-dependent licensing by toll-like receptor stimulation. Thus, these studies will provide significant new insight into how NK cells achieve self-tolerance.
| Sojka, Dorothy K; Plougastel-Douglas, Beatrice; Yang, Liping et al. (2014) Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife 3:e01659 |
| Ebihara, Takashi; Jonsson, A Helena; Yokoyama, Wayne M (2013) Natural killer cell licensing in mice with inducible expression of MHC class I. Proc Natl Acad Sci U S A 110:E4232-7 |
| Fogel, Leslie A; Yokoyama, Wayne M; French, Anthony R (2013) Natural killer cells in human autoimmune disorders. Arthritis Res Ther 15:216 |
| Peng, Hui; Jiang, Xiaojun; Chen, Yonglin et al. (2013) Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 123:1444-56 |
| Choi, Taewoong; Ferris, Stephen T; Matsumoto, Naoki et al. (2011) Ly49-dependent NK cell licensing and effector inhibition involve the same interaction site on MHC ligands. J Immunol 186:3911-7 |
| Elliott, Julie M; Yokoyama, Wayne M (2011) Unifying concepts of MHC-dependent natural killer cell education. Trends Immunol 32:364-72 |
| Vivier, Eric; Raulet, David H; Moretta, Alessandro et al. (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44-9 |
| Vargas, Claudia L; Poursine-Laurent, Jennifer; Yang, Liping et al. (2011) Development of thymic NK cells from double negative 1 thymocyte precursors. Blood 118:3570-8 |
| Cooper, Megan A; Yokoyama, Wayne M (2010) Memory-like responses of natural killer cells. Immunol Rev 235:297-305 |
| Higuchi, D A; Cahan, P; Gao, J et al. (2010) Structural variation of the mouse natural killer gene complex. Genes Immun 11:637-48 |
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