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News | 10/02/2026 | Research Spotlight

CD38 Shields CNS Tregs From Post-Inflammatory Stress

Using a mouse model of autoimmune neuroinflammation, the study shows that regulatory T cells persist in the CNS after the acute phase and are essential to prevent local relapses. The ectoenzyme CD38 equips these tissue-resident, antigen-specific Tregs to survive in an IL-2-poor, NAD⁺-rich environment by preserving high-affinity IL-2 receptor function.

This is a summary of Chen et al. CD38 endows local antigen-specific Treg cells with stress resilience for control of compartmentalized CNS inflammation. Published in Nature Immunology (2026). DOI: 10.1038/s41590-025-02416-z

The challenge

Regulatory T (Treg) cells are well known for preventing systemic autoimmunity, but much less is understood about what happens to Tregs that remain inside an organ after a major inflammatory episode. In multiple sclerosis and related settings, inflammation is often compartmentalized in the CNS, where immune cells can persist behind a blood–brain barrier and trigger flares even when peripheral immunity looks quiet. The post-inflammatory CNS is also a hostile niche: IL-2 becomes scarce as effector T cells contract, while extracellular NAD⁺ can promote deleterious ADP-ribosylation of surface proteins. How do tissue-resident, antigen-specific Tregs survive these combined stresses, and which molecular adaptations allow them to maintain local immune homeostasis long term?

Our approach

We induced experimental autoimmune encephalomyelitis (EAE) and combined fate mapping, photoconversion-based trafficking, and local (intracerebroventricular) Treg depletion to separate CNS-resident from systemic Treg function. We profiled CNS Tregs across disease phases by RNA-seq and flow cytometry, used adoptive transfers and mixed bone-marrow chimeras to test Treg-intrinsic CD38, and mechanistically probed NAD⁺/ARTC2.2-dependent ADP-ribosylation and IL-2 signaling.

Our findings

Tregs accumulated and persisted in specific CNS niches long after peak inflammation, while new Treg recruitment from lymph nodes largely ceased. Selective CNS depletion of post-inflammatory Tregs—not systemic depletion—provoked rapid, often lethal relapses driven by residual CNS effector T cells. Recovery-phase CNS Tregs showed a tissue-adapted program enriched for IL-2–STAT5 signaling and high CD25. CD38 proved indispensable for maintaining antigen-specific (MOG-reactive) CNS Tregs by preventing NAD⁺-driven ADP-ribosylation of IL-2Rα (CD25), thereby sustaining IL-2 sensitivity under stress.

The implications

The work pinpoints a tissue-specific “stress-tolerance” mechanism that stabilizes local immune control in the CNS. Targeting the CD38–NAD⁺–IL-2R axis could help prevent compartmentalized relapses without broadly suppressing systemic immunity.

Creating SyNergies

This study exemplifies SyNergy’s translational immunology: it links mechanistic biochemistry (NAD⁺ metabolism and ADP-ribosylation) with neuroinflammatory disease biology and tissue immunology. By dissecting what keeps regulatory circuits intact inside the CNS, it opens cross-disciplinary routes to biomarkers and targeted interventions in chronic, compartmentalized inflammation.