Hsin-Hsiang Chen, Sofia Tyystjärvi, Domingo Navarro, Ravi Kant, Tanja Groll, Ingrid Wagner, Helena Domínguez Moreno, Irene Bonafonte-Pardàs, Rupert Öllinger, Ali Maisam Afzali, Sylvia Heink, Lisa Charlotte Richter, Christopher Sie, Gildas Lepennetier, Lea R. Seeholzer, Katja Steiger, Doron Merkler, Rad Roland, Gunnar Schotta, Benjamin Schubert, Andreas Muschaweckh, Thomas Korn
Abstract Foxp3-expressing regulatory T (T reg ) cells protect against systemic autoimmunity. However, little is known about the significance of T reg cells in inflammation-experienced tissues. Here, we use an experimental autoimmune encephalomyelitis model and show that T reg 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 reg cells, but not systemic depletion of T reg 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 reg 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 reg cells. These ‘stress-tolerant’ CNS T reg cells impede the collapse of immune homeostasis in the CNS once acute inflammation is controlled.