Garg, G., Muschaweckh, A., Moreno, H., Vasanthakumar, A., Floess, S., Lepennetier, G., Oellinger, R., Zhan, Y. F., Regen, T., Hiltensperger, M., Peter, C., Aly, L., Knier, B., Palam, L. R., Kapur, R., Kaplan, M. H., Waisman, A., Rad, R., Schotta, G., Huehn, J., Kallies, A., and Korn, T. (2019). Cell Rep 26, 1854-1868.e5. doi: 10.1016/j.celrep.2019.01.070

Abstract: 

Foxp3⁺ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.