Spermidine/spermine N1-acetyltransferase controls tissue-specific regulatory T cell function in chronic inflammation

Abstract

SummaryRegulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, Tregsfail to control effector T cell responses. The causes of Tregdysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Tregfunction. Here we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to uncoverSAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Tregdysfunction during TH17-mediated inflammation. TregsexpressingSAT1exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived Tregsincreased expression ofSAT1leads to a loss of suppressive function and a switch to a TH17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a TH17 microenvironment. Finally, the potential therapeutic impact of targeting SSAT was demonstrated in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued Tregnumber and function in the skin and systemically. Together, these data show thatSAT1expression has severe functional consequences on Tregsand provides a novel target to treat chronic inflammatory skin disease.