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

Autor: Palmer, William H., Leaton, Laura Ann, Campos Codo, Ana, 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 P., Trowsdale, John, Getahun, Andrew, Rossjohn, Jamie, Cambier, John
Zdroj: Science Immunology; 2023, Vol. 8 Issue 84, p1-18, 18p
Abstrakt: 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. Editor's summary: Human killer immunoglobulin-like receptor (KIR) KIR3DL3 has been characterized as a conserved but polymorphic inhibitory KIR that can recognize HHLA2, but the receptor's function is unclear. Palmer et al. used high-resolution flow cytometry and single-cell transcriptomics to characterize KIR3DL3-expressing cells. They detected enriched expression of KIR3DL3 in γδ and CD8+ T cells but not NK cells. KIR3DL3-expressing cells were most frequently found in lungs and digestive tract and were rare in peripheral blood and thymus. Blood KIR3DL3+ T cells had an activated transitional memory phenotype and were considered hypofunctional. KIR3DL3 ligation could inhibit TCR-mediated stimulation, and KIR3DL3 polymorphisms were most likely to reduce expression. Together, KIR3DL3 expression appears to be up-regulated in parallel or downstream from TCR stimulation, and individuals can have varied KIR3DL3 expression, which can affect immune responses.—Christiana N. Fogg [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index