Abstract
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 γδ 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 γδ 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 γδ T cells and KCs at steady state increased the susceptibility to ultraviolet B radiation (UVR)-induced DNA damage and inflammation, two cancer-disposing factors.
Highlights
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
We have focused on intraepithelial lymphocytes (IELs), which compose one of the largest T cell compartments and are variably conserved in multiple tissues from agnathans to humans[8,9]
Here we showed that steady-state Vγ5Vδ1+ T cell antigen receptors (TCRs)-mediated interactions between dendritic epidermal T cells (DETCs) and KCs involve and depend on Skint[1]
Summary
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. This perspective has been transformed by examples of immune responses to non-microbial challenges and evidence that the steady-state immune system helps maintain physiological processes from metabolism to memory and barrier integrity[1–4] Many such interactions happen locally, involving immune cells permanently associated with non-lymphoid tissues[5–7]. IELs are disproportionately enriched in γδ T cells, which express site-specific TCRs, for example, Vγ5Vδ1 in mouse epidermis, Vγ7Vδn in mouse intestine and Vγ4Vδ1 in human intestine[9,13–15] Such selective repertoire focusing reflects the developmental dependence of IELs on cognate tissue-specific, epithelial-expressed BTNL heteromers. We show that constitutive DETC TCR-containing foci[22] align with and depend upon sustained epithelial expression of Skint[1] These interactions did not maintain DETC numbers, they preserved DETC and KC gene expression patterns and maintained steady-state epithelial barrier function. This offers a revised perspective of tissue immunosurveillance and of antigen receptor biology, which conventionally focuses on the recognition of molecules induced by change
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