# KIR and HLA in cis and trans cooperatively shape human NK education

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $449,000

## Abstract

PROJECT SUMMARY
Natural Killer (NK) cells are highly relevant in the setting of hematopoietic stem cell transplantation (HCT),
where their activity can drastically reduce the risk of relapse in leukemia patients. Despite advances in donor
selection to minimize transplant complications, leukemia relapse remains one of the most devastating causes
of transplant failure. There is a general lack of knowledge of how NK cell populations are educated for effector
function, leukemia recognition and clearance. While it is known that interaction between HLA class I molecules
and the inhibitory killer Ig-like receptors (KIR) are important for NK education or “licensing” for effector function,
the orientation of their interaction, the factors that contribute to the strength of their interaction, and the relative
contributions of donor and recipient HLA are not known.
 A major impediment to fundamental human NK studies has been the lack of in vivo models that
faithfully recapitulate NK education. A humanized NOD-RAG2IL2Rγc-/- mouse strain that exhibits HLA-B*27:05
successfully permits engraftment of mature NK cells and development of functional human NK cells from
CD34+ stem cells. Preliminary investigations reveal that in vivo environments expressing cognate HLA educate
developing and transferred KIR-expressing NK cells and enhance their long-term survival. In parallel, FRET
and RNAi technology reveals that cis-interaction between HLA and KIR intrinsic to the cell also facilitates NK
education. Evidence that HLA molecules can be transferred onto NK cells from adjacent cells provokes
investigation of trogocytosis as a mechanism by which trans HLA may permit education via cis ligation of KIR.
 Restriction of HLA expression to the hematopoietic or stromal compartments in bone marrow chimeras
will help define the relative contributions of donor and recipient HLA to NK licensing and persistence. Receptor-
ligand pairs known to bind in trans also interact in cis, and further clarification is required to understand how
these interactions influence NK function. Competition between cis-trans binding will test the hypothesis that cis
interactions facilitate NK responsiveness by shielding KIR from ligation of trans HLA. NK cells with and without
non-native HLA expression will be functionally tested to better understand how trogocytosis contributes to NK
education after continuous or interrupted exposure to cognate HLA. Finally, experimental findings from the
humanized mouse model and in vitro studies will be verified in a fully human system using NK cells obtained
from patients who have received an HLA-mismatched umbilical cord blood transplant.
 These goals will advance our understanding of fundamental molecular requirements for NK education
and acquisition of effector function. A deeper understanding of licensing by HLA provided in cis and trans will
inform donor selection in hematopoietic cell transplantation and adoptive NK cell therapies for the treatment of
cancer...

## Key facts

- **NIH application ID:** 9967998
- **Project number:** 5R01AI125651-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** KATHARINE C HSU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $449,000
- **Award type:** 5
- **Project period:** 2016-07-03 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967998

## Citation

> US National Institutes of Health, RePORTER application 9967998, KIR and HLA in cis and trans cooperatively shape human NK education (5R01AI125651-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9967998. Licensed CC0.

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