Monin, L.; Cano, F.; Axford, J.; Cooper, G.; Hernandez-Mir, G.; Okkenhaug, K.; Hayday, A. C.

Intraepithelial lymphocytes (IEL) are conserved across vertebrates and commonly enriched in {gamma}{delta} T cells. Several such {gamma}{delta} IELs depend upon homeostatic interactions of their T cell receptors (TCRs) with butyrophilin-like (BTNL) proteins expressed by healthy enterocytes and colonocytes. What limits such interactions from inducing full-blown T cell activation which would disrupt barrier integrity is unknown. Here, using primary IEL, we describe an atypical TCR signalling pathway (Signal 1) downstream of BTNL engagement, that fails to activate either global protein synthesis or cell proliferation. This attenuation could be overcome by provision of a co-stimulator (Signal 2) or inflammatory cytokines (Signal 3). It could also be relieved cell-intrinsically by blocking a lipid phosphatase. These findings can, at least in part, explain how extrinsic and intrinsic regulators permit IEL to be constitutively active in healthy tissues and additionally make full-blown responses to adaptive TCR ligands during tissue perturbation.