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

Summary Regulatory T cells (T regs ) are a critical immune component guarding against excessive inflammatory responses. During chronic inflammation, T regs fail to control effector T cell responses. The causes of T reg dysfunction in these diseases are poorly characterized and therapies are aimed at blocking aberrant effector responses rather than rescuing T reg 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 T reg dysfunction during T H 17-mediated inflammation. T regs expressing SAT1 exhibit a tissue-specific inflammation signature and show a proinflammatory effector-like profile. In CRISPRa on healthy human skin-derived T regs increased expression of SAT1 leads to a loss of suppressive function and a switch to a T H 17-like phenotype. This phenotype is induced by co-receptor expression on keratinocytes exposed to a T H 17 microenvironment. Finally, the potential therapeutic impact of targeting SSAT was demonstrated in a mouse model of skin inflammation by inhibiting SSAT pharmacologically, which rescued T reg number and function in the skin and systemically. Together, these data show that SAT1 expression has severe functional consequences on T regs and provides a novel target to treat chronic inflammatory skin disease.