The polyamine-regulating enzyme SSAT1 impairs tissue regulatory T cell function in chronic cutaneous inflammation
Regulatory T (T<sub>reg</sub>) cells are a critical immune component guarding against excessive inflammation. T<sub>reg</sub> cell dysfunction can lead to chronic inflammatory diseases with current therapies aimed at inhibiting effector T cells rather than rescuing T<sub>reg</sub> 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<sub>reg</sub> cell dysfunction. CRISPRa-driven SAT1 expression in human skin-derived T<sub>reg</sub> cells impaired their suppressive function and induced a pro-inflammatory phenotype. During cutaneous type-17 inflammation, keratinocyte 4-1BBL induces SAT1 on T<sub>reg</sub> cells. In a mouse model of psoriasis, pharmacological inhibition of SSAT rescued T<sub>reg</sub> cell number and function. Together, these data show that SAT1 expression has severe functional consequences on T<sub>reg</sub> cells and suggest a therapeutic target to treat chronic inflammatory disease.
Authors
- Daniel Malzl (ORCID: https://orcid.org/0000-0001-5765-6375)
- Elisabeth Ponweiser
- Erwin F. Wagner (ORCID: https://orcid.org/0000-0001-7872-0196)
- Davide Seruggia (ORCID: https://orcid.org/0000-0001-5014-0499)
- Lisa Kleißl (ORCID: https://orcid.org/0000-0001-8011-796X)
- Katja Knapp
- Georg Stary (ORCID: https://orcid.org/0000-0003-1746-4250)
- Jörg Menche (ORCID: https://orcid.org/0000-0002-1583-6404)
- Teresa Neuwirth
- Christian Freystätter (ORCID: https://orcid.org/0000-0002-3144-7126)
- Arvand Haschemi (ORCID: https://orcid.org/0000-0001-9532-3205)
- Ana P. Kutschat (ORCID: https://orcid.org/0000-0002-6360-873X)
- Panagiota Tsokkou (ORCID: https://orcid.org/0000-0001-8095-2615)
- Nara Marella (ORCID: https://orcid.org/0000-0001-5254-6089)
- Baerbel Reininger
- A. Gabriel
Institutions
- University of Vienna (AT)
- Austrian Academy of Sciences (AT)
- Max Perutz Labs (AT)
- CeMM Research Center for Molecular Medicine (AT)
- Community College of Rhode Island (US)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Immunity
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1016/j.immuni.2025.02.011
- Citations
- 18
- Primary Topic
- Polyamine Metabolism and Applications
- Type
- article
- Field-Weighted Citation Impact
- 14.51
Funders
- Vienna Science and Technology Fund
- Austrian Science Fund
- LEO Fondet
- HORIZON EUROPE European Research Council