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.