Regulatory T (Treg) cells expressing CD4 and Foxp3 are the main regulators of autoimmune diseases. However, the temporal and spatial characteristics of tissue-specific autoimmune suppression mediated by Treg cells have not yet been clearly revealed. In a study recently published in the journal PNAS, Benoît L. Salomon's team from Sorbonne University in France further revealed the role of tumor necrosis factor receptor 2 (TNFR2) signaling in Treg cells during multiple sclerosis (EAE).
The authors found that Treg cells expressing TNFR2 are critical to suppress the severity of the disease at the peak of EAE, but have no effect on T cell activation in the lymphatic tissues at the initial stage of disease onset. In terms of mechanism, TNFR2 signaling can maintain functional Treg cells, allowing them to continuously express CTLA-4 and Blimp-1, thereby actively inhibiting the expansion of pathogenic T cells in the inflamed central nervous system. The treatment of EAE mice with TNF and TNFR2 agonists and antagonists further confirmed the regulatory role of Treg cells in key stages.
First, the authors constructed and bred Foxp3-CreTnfrsf1b fl (cKO) mice. TNFR2 in the Treg cells of cKO mice was specifically knocked out. By inducing the occurrence of EAE, the authors found that the knockout of TNFR2 would significantly affect the homeostasis of Treg cells and lead to further exacerbation of EAE. Furthermore, the authors constructed an induced mutant mouse Foxp3Cre-ERT2Tnfrsf1bfl (icKO), which will knock out TNFSFR2 after tamoxifen induction. The author first induced EAE on wild-type and icKO mice, and added tamoxifen to induce induction on day 7-14.
After that, the author studied the number of Tregs and gene expression in the CNS region of wild-type and icKO mice. The results showed that although there was no significant difference in the number of Treg cells in the CNS region of icKO and wild-type mice, the expression levels of CTLA-4 and Blimp-1 of Treg cells in mutant mice were significantly down-regulated, its activation level has also been significantly affected.
Afterward, the author analyzed the activation state of conventional T cells (Tconv) in the brain after EAE induction in mice, and the results showed that the defect of TNFR2 in Treg cells would increase the activation level of Tconv and its pathology.
Finally, through T cell transplantation experiments, the author found that the presence of TNFR2 in Tregs can inhibit the severity of the disease in the late stage of EAE (10 days). Artificially inhibiting the signal of TNFR2 in Treg by TNF injection will increase the severity of the disease and decrease the survival rate of mice.
In summary, a series of experimental evidence show that endogenous Treg cells can specifically inhibit autoimmune diseases by acting on target tissues during the development of EAE inflammation. This discovery provides mechanistic insights into some of the adverse effects of anti-TNF therapy on patients.