Natural killer (NK) cell tolerance to self is incompletely understood despite wide-spread acceptance of the now familiar ?missing-self? hypothesis. Serving as a guiding principle for several decades, it proposed that NK cells survey tissues for ubiquitously expressed major histocompatibility complex class I (MHC-I) molecules as self. Normal levels of MHC-I do not allow NK cell attack but if MHC-I is down-regulated in a pathologic event, NK cells attack. The applicant and his laboratory discovered the Ly49 family of receptors specific for MHC-I molecules and that inhibit NK cell activation receptor function, providing a molecular explanation for the missing-self hypothesis. However, the missing-self hypothesis provides a few predictions that were not observed, including the hypo-responsiveness of NK cells in MHC-I-deficient hosts, rather than hyper-reactive NK cells. This can now be explained by more recent findings from the applicant's laboratory that the Ly49 receptors have a second function to license or educate NK cells to self-MHC-I, thereby generating appropriate self-tolerant NK cells. Other unresolved issues regarding missing-self and NK cell tolerance remain unresolved, such as if all tissues are protected by MHC-I from NK cell attack, the tissues expressing MHC-I that confer licensing, and if Ly49s are solely responsible for licensing. Herein the applicant proposes to study NK cell tolerance utilizing novel mice recently generated in his laboratory. In particular, the Specific Aims of this proposal are to study: 1) Tissue-specificity and temporal aspects of missing-self protection; 2) Tissue-specific induction and maintenance of licensed NK cells; and 3) Role of Ly49s in licensing by self-MHC. These studies will enhance our understanding of NK cell tolerance and the missing-self hypothesis.

Public Health Relevance

This project deals with natural killer (NK) cells which are immune cells that can kill cancer or infected cells. In addition, NK cells can also produce inflammatory cytokines that can help the body?s immune defense. However, these functions of NK cells must be constrained so that they do not attack normal cells which could lead to inadvertent tissue damage. In other words, NK cells must be tolerant to normal cells. The current proposal will examine the fundamental principle that underlies current thinking on how NK cells achieve this tolerant state.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Transplantation, Tolerance, and Tumor Immunology Study Section (TTT)
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Lapham, Cheryl K
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Bern, Michael D; Beckman, Diana L; Ebihara, Takashi et al. (2017) Immunoreceptor tyrosine-based inhibitory motif-dependent functions of an MHC class I-specific NK cell receptor. Proc Natl Acad Sci U S A 114:E8440-E8447