Adaptive-like features of the γδ TCR couple chronic BTNL recognition to NK-like tissue immunity

Intestinal intraepithelial V{gamma}4 {gamma}{delta} lymphocytes (IELs) continuously bind to the steady presence of the epithelial ligand BTNL3/8 via T cell receptor (TCR) determinants that are encoded by the TCR's germline. Although they share similarities with innate-like T cells, such as NKT cells, V{gamma}4 IELs only experience ligand engagement after thymic development.

Unlike conventional {beta} T cells, V{gamma}4 IELs maintain persistent ligand engagement without experiencing exhaustion. Through the use of biophysical, functional, and multimodal single-cell methods, researchers have uncovered how V{gamma}4 IELs tackle this challenge. While germline-encoded TCR regions generally facilitate BTNL3 recognition, successful activation necessitates supplementary non-germline TCR elements that authorize responsiveness to BTNL3/8 and facilitate local selection within the gut.

Rather than contributing to exhaustion, the interaction with BTNL3/8 directly stimulates the expression of an NK-like program characterized by adaptor molecules that facilitate innate-like signaling in healthy tissue. These discoveries demonstrate how the unique combination of innate and adaptive features of the {gamma}δ TCR enables sustained tissue specialization amidst persistent physiological ligand engagement.