Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity
Year: 2026
Type: preprint
Abstract: Intestinal Vγ4 γδ intraepithelial lymphocytes (IELs) persistently bind the constitutively expressed epithelial ligand BTNL3/8 through germline-encoded T cell receptor (TCR) determinants. While they resemble innate-like T cells such as NKT cells, unlike these populations, Vγ4 IELs encounter ligand only after thymic development. Moreover, unlike conventional αβ T cells, Vγ4 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how Vγ4 IELs address this challenge. While germline-encoded TCR regions broadly mediate BTNL3 recognition, productive activation requires additional non-germline TCR features that license responsiveness to BTNL3/8 and enable local selection in the gut. Rather than driving exhaustion, BTNL3/8 reactivity directly promotes expression of an NK-like program marked by adaptor molecules that license innate-like signaling in healthy tissue. These findings reveal how combined innate and adaptive features of the γδTCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.
Authors: Benjamin D McDonald, Hope D Anderson, Toufic Mayassi, Chhon Ling Sok, Veronica Locher, Magdalena Justyniarska, Megan E Borregard, Caroline Kaiser, Kristin Ladell, James E McLaren, David A Price, Narutoshi Hibino, Andrew S Koh, Jamie Rossjohn, Benjamin S Gully, Samantha J Riesenfeld, Bana Jabri
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Molecular and Cellular Biology Training, Graduate Research Fellowship Program (GRFP), The immunopathogenesis of Epstein-Barr virus-associated malignancies., The immunopathogenesis of Epstein-Barr virus-associated malignancies., Digestive Health and Diseases (DHD) Training Grant, Innate and adaptive immunity in celiac disease, Epigenesis of Cell Fate Potential
OpenAlex ID: W7214206382