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Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells
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
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
Author
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
Cambier, John
Loh, Liyen
Norman, Paul J.
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
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.
Keywords
KIR3DL3, HHLA2, B7H7, T cells, TCR, IEL, intestine, lung, polymorphism
Date
2023
Type
Journal article
Journal
Book
Volume
8
Issue
84
Page Range
1-18
Article Number
ACU Department
Marketing and Communications
Research Office
Research Office
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Controlled
Controlled
Controlled
Notes
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.
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.