CD38 endows local antigen-specific Treg cells with stress resilience for control of compartmentalized CNS inflammation

Foxp3-expressing regulatory T (T_reg) cells protect against systemic autoimmunity. However, little is known about the significance of T_regcells in inflammation-experienced tissues. Here, we use an experimental autoimmune encephalomyelitis model and show that T_regcells 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_regcells, but not systemic depletion of T_regcells, 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_regcells 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_regcells. These 'stress-tolerant' CNS T_regcells impede the collapse of immune homeostasis in the CNS once acute inflammation is controlled.

https://doi.org/10.1038/s41590-025-02416-z