alpha/beta/gamma/delta T cells play a vital role in fetal human skin development and immunity

T cells in adult human skin play a pivotal role in the defense against pathogens and tumors. While T cells can also be found in fetal human skin, little is known about their phenotype and function. Using single cell analyses, here we identify an unconventional naive T cell population expressing both alpha/beta and gamma/delta T cell receptors (TCRs) that was markedly enriched within early fetal skin and intestine but was untraceable in other fetal organs and peripheral blood. TCR sequencing data revealed that double-positive (DP) T cells displayed marginal or no overlap of CDR3 sequences with single-positive alpha/beta T cells. Gene signature, cytokine profile and in silico receptor-ligand interaction studies indicated that DP T cells contribute to skin development early in life. Finally, DP T cells were phosphoantigen-responsive suggesting that these cells participate in the protection of the fetus against pathogens in case of intrauterine infections. Together, our analyses unveil a unique and hitherto unrecognized cutaneous T cell type within the native skin microenvironment and point to fundamental differences in the adaptive immune surveillance of developing and adult human skin. Three samples of human embryonic skin. **Submitters declare that they can not provide raw sequencing data, as the data contain identifiable information.