Normality sensing licenses local T cells for innate-like tissue surveillance

Hayday and colleagues show that sustained Skint1-dependent interactions between murine intraepidermal gamma delta T cells and keratinocytes are required to maintain the homeostatic barrier function and phenotype of the intraepidermal gamma delta T cells, including their preparedness to respond appropriately to epidermal challenges. The increasing implication of lymphocytes in general physiology and immune surveillance outside of infection poses the question of how their antigen receptors might be involved. Here, we show that macromolecular aggregates of intraepidermal gamma delta T cell antigen receptors (TCRs) in the mouse skin aligned with and depended on Skint1, a butyrophilin-like (BTNL) protein expressed by differentiated keratinocytes (KCs) at steady state. Interruption of TCR-mediated 'normality sensing' had no impact on gamma delta T cell numbers but altered their signature phenotype, while the epidermal barrier function was compromised. In addition to the regulation of steady-state physiology, normality sensing licensed intraepidermal T cells to respond rapidly to subsequent tissue perturbation by using innate tumor necrosis factor (TNF) superfamily receptors. Thus, interfering with Skint1-dependent interactions between local gamma delta T cells and KCs at steady state increased the susceptibility to ultraviolet B radiation (UVR)-induced DNA damage and inflammation, two cancer-disposing factors.

Automated summary

This study demonstrates that the sustained interactions between keratinocytes and intraepidermal γδT cells are crucial for maintaining the homeostatic barrier function and phenotype of the γδT cells. These interactions also enable the γδT cells to respond rapidly to tissue perturbation.