The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation

Immunity. 2025 Mar 11;58(3):632-647.e12. doi: 10.1016/j.immuni.2025.02.011. Epub 2025 Feb 28.

Abstract

Regulatory T (Treg) cells are a critical immune component guarding against excessive inflammation. Treg cell dysfunction can lead to chronic inflammatory diseases with current therapies aimed at inhibiting effector T cells rather than rescuing Treg 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 Treg cell dysfunction. CRISPRa-driven SAT1 expression in human skin-derived Treg cells impaired their suppressive function and induced a pro-inflammatory phenotype. During cutaneous type-17 inflammation, keratinocyte 4-1BBL induces SAT1 on Treg cells. In a mouse model of psoriasis, pharmacological inhibition of SSAT rescued Treg cell number and function. Together, these data show that SAT1 expression has severe functional consequences on Treg cells and suggest a therapeutic target to treat chronic inflammatory disease.

Keywords: chronic inflammation; polyamine metabolism; psoriasis; regulatory T cells.

MeSH terms

  • Acetyltransferases* / genetics
  • Acetyltransferases* / immunology
  • Acetyltransferases* / metabolism
  • Animals
  • Chronic Disease
  • Disease Models, Animal
  • Humans
  • Inflammation* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Polyamines* / metabolism
  • Psoriasis* / immunology
  • Psoriasis* / pathology
  • Skin* / immunology
  • Skin* / pathology
  • T-Lymphocytes, Regulatory* / immunology
  • T-Lymphocytes, Regulatory* / metabolism

Substances

  • Acetyltransferases
  • diamine N-acetyltransferase
  • Polyamines