The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation
Teresa Neuwirth, Daniel Malzl, Katja Knapp, Panagiota Tsokkou, Lisa Kleißl, Anna Gabriel, Baerbel Reininger, Christian Freystätter, Nara Marella, Ana P. Kutschat, Elisabeth Ponweiser, Arvand Haschemi, Davide Seruggia, Jörg Menche, Erwin F. Wagner, Georg Stary
Abstract
Regulatory T (T reg ) cells are a critical immune component guarding against excessive inflammation. T reg cell dysfunction can lead to chronic inflammatory diseases with current therapies aimed at inhibiting effector T cells rather than rescuing T reg cell function. We utilized single-cell RNAsequencing data from patients with chronic inflammation to identify SAT1 , the gene encoding spermidine/spermine N1-acetyltransferase (SSAT), as a driver of skin-resident T reg cell dysfunction. CRISPRa-driven SAT1 expression in human skin-derived T reg cells impaired their suppressive function and induced a pro-inflammatory phenotype. During cutaneous type-17 inflammation, keratinocyte 4-1BBL induces SAT1 on T reg cells. In a mouse model of psoriasis, pharmacological inhibition of SSAT rescued T reg cell number and function. Together, these data show that SAT1 expression has severe functional consequences on T reg cells and suggest a therapeutic target to treat chronic inflammatory disease.