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

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• Killer cell immunoglobulin-like receptors (KIR) typically function on natural killer (NK) cells, recognizing HLA class I ligands.
• KIR3DL3, an inhibitory KIR, binds the B7 family ligand HHLA2 and is a target for immune checkpoint inhibition.
• The expression and function of KIR3DL3 have remained largely uncharacterized.

Purpose of the Study:

• To investigate the expression profile and biological function of KIR3DL3.
• To determine the cellular distribution and characteristics of KIR3DL3-expressing cells.
• To explore the implications of KIR3DL3 expression and its variants for immune checkpoint targeting.

Main Methods:

• Extensive transcriptomic analysis to identify KIR3DL3 expression.
• High-resolution flow cytometry and single-cell transcriptomics to characterize KIR3DL3+ T cells.
• Analysis of T cell receptor (TCR) usage and functional assays including KIR3DL3 ligation.

Main Results:

• KIR3DL3 is highly expressed in γδ and CD8+ T cells, not NK cells, with enriched presence in the lungs and digestive tract.
• KIR3DL3+ T cells exhibit an activated transitional memory phenotype and reduced functionality.
• TCR-mediated T cell stimulation can be inhibited by KIR3DL3 ligation, and certain genetic variants affect KIR3DL3 expression levels.

Conclusions:

• KIR3DL3 is upregulated during unconventional T cell activation and its expression is variable among individuals.
• Findings suggest KIR3DL3 plays a role in T cell regulation and has implications for personalized KIR3DL3/HHLA2 immune checkpoint inhibition strategies.