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

Regulatory T cells (Tregs) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, Tregs fail to control effector T cell responses. The causes of Treg dysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing Treg function. Here we utilized single-cell RNA sequencing data from patients suffering from chronic skin and colon inflammation to uncover SAT1, the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a novel marker and driver of skin-specific Treg dysfunction during TH17-mediated inflammation. Tregs expressing SAT1 exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived Tregs increased expression of SAT1 leads 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 Treg number and function in the skin and systemically. Together, these data show that SAT1 expression has severe functional consequences on Tregs and provides a novel target to treat chronic inflammatory skin disease.