Adaptive immunity to ancient retroelements controls the skin tissue threshold of activation

A symbiotic dialogue between the microbiota and host is essential to promote protective immune responses in the skin. Integrated retroviral elements, or retrotransposons (RTNs), comprise up to 45% of the human genome. We previously found that immune responses to the skin microbiota are dependent on the reactivation and keratinocyte-intrinsic sensing of RTNs. Here, we explored the possibility that RTNs may also represent a source of antigens recognized by the skin adaptive immune system. We first established a model of sterile injury, where topical application of a mild detergent reactivated RTNs, and recruited CD8 T cells to the skin in an RTN-dependent manner. RNAseq analysis of RTN expression revealed Langerhans cells (LCs) have the most abundant RTN expression amongst skin dendritic cells. Our work demonstrated that CD8 T cell responses to sterile injury were entirely dependent on LCs, supporting the idea that LCs could present RTN antigens to CD8 T cells. To identify RTN-specific T cells, we selected peptides that were uniquely expressed in LCs, but not in thymic epithelial cells which mediate negative selection. Several peptides promoted cytokine production from injury-elicited CD8 T cells, confirming the presence of RTN-reactive CD8 T cells in the skin. RNA-seq analysis suggests RTN-specific CD8 T cells may contribute to wound repair and immunoregulation. Thus, mild stress, such as that induced by mild detergent, is sufficient to promote adaptive immunity to defined antigens derived from RTNs. Our work also proposes that homeostatic immunity to ancient retroviruses promotes a defined class of T cells responses aimed at maintaining barrier integrity in response to daily stressors encountered by the skin.