Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity
- 1Pritzker School of Molecular Engineering, University of Chicago, Chicago, IL, USA
Abstract
Intestinal V{gamma}4 {gamma}{delta} 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, V{gamma}4 IELs encounter ligand only after thymic development. Moreover, unlike conventional {beta} T cells, V{gamma}4 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how V{gamma}4 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 {gamma}{delta}TCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.
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BibTeX
@misc{mcdonald2026adaptivelike,
title = {{Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity}},
author = {B. D. McDonald and H. D. Anderson and T. Mayassi and C. L. Sok and V. Locher and M. Justyniarska and M. E. Borregard and C. Kaiser and K. Ladell and J. E. McLaren and D. A. Price and N. Hibino and A. S. Koh and J. Rossjohn and B. S. Gully and S. J. Riesenfeld and B. Jabri},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.751481},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.751481v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity
AU - B. D. McDonald
AU - H. D. Anderson
AU - T. Mayassi
AU - C. L. Sok
AU - V. Locher
AU - M. Justyniarska
AU - M. E. Borregard
AU - C. Kaiser
AU - K. Ladell
AU - J. E. McLaren
AU - D. A. Price
AU - N. Hibino
AU - A. S. Koh
AU - J. Rossjohn
AU - B. S. Gully
AU - S. J. Riesenfeld
AU - B. Jabri
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.751481
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.751481v1
AB - Intestinal V{gamma}4 {gamma}{delta} 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, V{gamma}4 IELs encounter ligand only after thymic development. Moreover, unlike conventional {beta} T cells, V{gamma}4 IELs sustain persistent physiological ligand engagement without becoming exhausted. Here, using biophysical, functional, and multimodal single-cell approaches, we show how V{gamma}4 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 {gamma}{delta}TCR enable durable tissue specialization under conditions of persistent physiological ligand engagement.
ER -