CD38 endows local antigen-specific Foxp3+ Treg cells with stress resilience for compartmentalized control of CNS inflammation
Foxp3-expressing regulatory T (Treg) cells protect from systemic autoimmunity. However, little is known about the significance of Treg cells in inflammation-experienced tissues. Using experimental autoimmune encephalomyelitis (EAE), we show that Treg cells accumulate and persist in the central nervous system (CNS) until long after the resolution of the bulk of the inflammatory infiltrate. CNS-specific local depletion of post-inflammatory Treg cells, but not systemic depletion of Treg cells, immediately rekindles autoimmune inflammatory flares in the CNS by residual local effector T cells. Expression of the NAD-consuming ecto-enzyme CD38 is crucial for the functional adaptation of post-inflammatory CNS Treg cells to a stressful microenvironment, in which access to IL-2 is limited. CD38 counteracts ADP-ribosylation of the IL-2R and, thus, maintains its high sensitivity to IL-2. Their fully functional high-affinity IL-2 receptor prevents the loss of tissue-resident antigen-specific Treg cells. These "stress-tolerant" CNS Treg cells impede the collapse of immune homeostasis in the CNS once acute inflammation is controlled. Overall design: We profiled the transcriptome of spleen, visceral adipose tissue, and CNS Foxp3+ Treg cells, along with Foxp3- conventional Th cells (Tconv), isolated from Foxp3 (GFP) reporter mice at different EAE disease stages (Naïve, Pre-onset, Peak, Recovery) using bulk RNA-seq. Additionally, we employed the same experimental design to isolate cells from Foxp3ERT2-Cre Rosa26LSL-tdTomato mice at the Recovery stage. Utilizing Tamoxifen labeling and the Foxp3 fate-mapping system, we sorted stable (Foxp3-GFP+, tdTomato+) and unstable (Foxp3-GFP+, tdTomato-) populations and performed bulk RNA-seq analysis.