The overall goal of this proposal is to better understand how natural killer (NK) cells are tolerant to self in order to gain insight into how NK cells control tumors and infections. The major guiding principle for NK cell tolerance is the missing-self hypothesis which postulates that NK cells survey all tissues for normal expression of MHC class I (MHC-I) molecules which prevents NK cell attack. In a pathologic event, MHC-I is down- regulated and NK cells kill the affected target cell. This is due to inhibitory NK cell receptors that recognize target cell MHC-I molecules and block NK cell activation. However, a caveat with the missing-self hypothesis is that MHC-I-deficient hosts do not exhibit auto-reactive NK cells. Instead the NK cells do not function normally, demonstrating diminished capacity to produce cytokines when triggered through their activation receptors. The applicant's laboratory has provided previous evidence indicating that NK cells are educated through self-MHC-I recognition by their MHC-specific inhibitory receptors, in a process termed licensing. In the current application, they provide additional evidence that require modification of the missing-self hypothesis. They show that when NK cells are unrestrained to attack MHC-I-deficient cells, they target only certain cells, suggesting that missing-self applies only to certain tissues. Therefore, the specific aims of this proposal are to study: 1) Tests of missing-self in parabiotic mice;2) Tissue-specific constraints of missing-self;3) Mechanisms by which NK cells are licensed by self-MHC. These studies will provide significant insight into the NK cells and self-tolerance which will inform clinical studies designed to harness NK cells against tumors.

Public Health Relevance

This project aims to better understand how a component of the immune system, the natural killer (NK) cell, is controlled. NK cells contain potent weapons to attack cancers and infection but they are prevented from attacking normal tissues. Understanding this control will enable scientists to harness NK cells for treatment of cancers and infections where it will be beneficial to unleash NK cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033903-21
Application #
8518218
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Miller, Lara R
Project Start
1992-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
21
Fiscal Year
2013
Total Cost
$285,760
Indirect Cost
$97,760
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
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
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
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
Jonsson, A Helena; Yang, Liping; Kim, Sungjin et al. (2010) Effects of MHC class I alleles on licensing of Ly49A+ NK cells. J Immunol 184:3424-32
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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