Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells

Journal article


Palmer, William H., Leaton, Laura Ann, Codo, Ana Campos, Crute, Bergren, Roest, James, Zhu, Shiying, Petersen, Jan, Tobin, Richard P., Hume, Patrick S., Stone, Matthew, van Bokhoven, Adrie, Gerich, Mark E., McCarter, Martin D., Zhu, Yuwen, Janssen, William J., Vivian, Julian Philip, Trowsdale, John, Getahun, Andrew, Rossjohn, Jamie, ... Norman, Paul J.. (2023). Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells. Science Immunology. 8(84), pp. 1-18. https://doi.org/10.1126/sciimmunol.ade5343
AuthorsPalmer, William H., Leaton, Laura Ann, Codo, Ana Campos, Crute, Bergren, Roest, James, Zhu, Shiying, Petersen, Jan, Tobin, Richard P., Hume, Patrick S., Stone, Matthew, van Bokhoven, Adrie, Gerich, Mark E., McCarter, Martin D., Zhu, Yuwen, Janssen, William J., Vivian, Julian Philip, Trowsdale, John, Getahun, Andrew, Rossjohn, Jamie, Cambier, John, Loh, Liyen and Norman, Paul J.
Abstract

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8+ T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3+ T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.

KeywordsKIR3DL3; HHLA2; B7H7; T cells; TCR; IEL; intestine; lung; polymorphism
Year01 Jan 2023
JournalScience Immunology
Journal citation8 (84), pp. 1-18
PublisherAmerican Association for the Advancement of Science
ISSN2470-9468
Digital Object Identifier (DOI)https://doi.org/10.1126/sciimmunol.ade5343
Web address (URL)https://www.science.org/doi/10.1126/sciimmunol.ade5343
Open accessPublished as non-open access
Research or scholarlyResearch
Page range1-18
Author's accepted manuscript
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All rights reserved
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License
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Output statusPublished
Publication dates
Online22 Aug 2022
Publication process dates
Accepted07 Jul 2022
Deposited12 Mar 2024
Additional information

Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Original RNA-seq data have been deposited to GEO: GSE232917. All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials and at https://doi.org/10.6084/m9.figshare.c.6651410.v2 alongside any bespoke code used for analysis. Cell lines and other materials are available upon request.

Place of publicationUnited States
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