# Natural Killer Cell Tolerance to Self

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $508,164

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 9856978
- **Project number:** 5R01AI129545-04
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Wayne M. Yokoyama
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,164
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856978

## Citation

> US National Institutes of Health, RePORTER application 9856978, Natural Killer Cell Tolerance to Self (5R01AI129545-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9856978. Licensed CC0.

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