CD38 endows local antigen-specific Treg cells with stress resilience for control of compartmentalized CNS inflammation
Foxp3-expressing regulatory T (T<sub>reg</sub>) cells protect against systemic autoimmunity. However, little is known about the significance of T<sub>reg</sub> cells in inflammation-experienced tissues. Here, we use an experimental autoimmune encephalomyelitis model and show that T<sub>reg</sub> cells accumulate and persist in the central nervous system (CNS) long after the resolution of the bulk of the inflammatory infiltrate. CNS-specific depletion of postinflammatory T<sub>reg</sub> cells, but not systemic depletion of T<sub>reg</sub> cells, results in autoimmune inflammatory flares in the CNS by residual local effector T cells. Expression of the NAD-consuming ectoenzyme CD38 is crucial for the functional adaptation of postinflammatory CNS T<sub>reg</sub> cells to a stressful microenvironment, in which access to interleukin-2 (IL-2) is limited. CD38 counteracts ADP-ribosylation of the IL-2 receptor and thus maintains its high sensitivity to IL-2. This fully functional high-affinity IL-2 receptor prevents the loss of tissue-resident antigen-specific T<sub>reg</sub> cells. These 'stress-tolerant' CNS T<sub>reg</sub> cells impede the collapse of immune homeostasis in the CNS once acute inflammation is controlled.
Authors
- Sofia Tyystjärvi (ORCID: https://orcid.org/0000-0002-5057-1923)
- Ingrid Wagner (ORCID: https://orcid.org/0000-0003-4437-9799)
- Andreas Muschaweckh (ORCID: https://orcid.org/0000-0002-6870-1378)
- Gildas Lepennetier (ORCID: https://orcid.org/0000-0002-1899-3149)
- Rupert Öllinger (ORCID: https://orcid.org/0000-0002-2292-5982)
- Irene Bonafonte-Pardàs (ORCID: https://orcid.org/0009-0005-1053-1838)
- Ravi Kant (ORCID: https://orcid.org/0000-0002-4424-2744)
- Domingo Navarro (ORCID: https://orcid.org/0009-0007-4825-8624)
- Helena Domínguez Moreno (ORCID: https://orcid.org/0000-0003-2792-5874)
- Doron Merkler (ORCID: https://orcid.org/0000-0002-0247-2007)
- Ali Maisam Afzali (ORCID: https://orcid.org/0000-0002-3256-5298)
- Christopher Sie (ORCID: https://orcid.org/0000-0002-8066-7539)
- Tanja Groll (ORCID: https://orcid.org/0000-0002-9049-9145)
- Gunnar Schotta (ORCID: https://orcid.org/0000-0003-4940-6135)
- Rad Roland (ORCID: https://orcid.org/0000-0002-6849-9659)
- Hsin-Hsiang Chen (ORCID: https://orcid.org/0000-0003-2496-0607)
- Lea R. Seeholzer
- Benjamin Schubert
- Sylvia Heink
- Lisa Charlotte Richter
- Thomas Korn
- Katja Steiger
Institutions
- Helmholtz Zentrum München (DE)
- University of Hyderabad (IN)
- Munich Cluster for Systems Neurology (DE)
- Technical University of Munich (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-01-29
- DOI
- https://doi.org/10.1038/s41590-025-02416-z
- Citations
- 1
- Primary Topic
- Calcium signaling and nucleotide metabolism
- Type
- article
- Field-Weighted Citation Impact
- 29.96
Funders
- Deutsche Forschungsgemeinschaft
- Technische Universität München
- Universität Konstanz