Tissue-restricted control of established central nervous system autoimmunity by TNF receptor 2–expressing Treg cells

Abstract

CD4+Foxp3+ regulatory T (Treg) cells are central modulators of autoimmune diseases. However, the timing and location of Treg cell–mediated suppression of tissue-specific autoimmunity remain undefined. Here, we addressed these questions by investigating the role of tumor necrosis factor (TNF) receptor 2 (TNFR2) signaling in Treg cells during experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We found that TNFR2-expressing Treg cells were critical to suppress EAE at peak disease in the central nervous system but had no impact on T cell priming in lymphoid tissues at disease onset. Mechanistically, TNFR2 signaling maintained functional Treg cells with sustained expression of CTLA-4 and Blimp-1, allowing active suppression of pathogenic T cells in the inflamed central nervous system. This late effect of Treg cells was further confirmed by treating mice with TNF and TNFR2 agonists and antagonists. Our findings show that endogenous Treg cells specifically suppress an autoimmune disease by acting in the target tissue during overt inflammation. Moreover, they bring a mechanistic insight to some of the adverse effects of anti-TNF therapy in patients.

TNFa and IL-6 promote ex-vivo proliferation of lineage-committed human regulatory T cells

“…The ability of Tregs to respond and dampen inflammation is essential for the resolution of immune responses and restoring normal immune homeostasis. Results from this study are consistent with reports in mice on the important function of TNFa-TNFR2 axis in Treg function at site of inflammation in models of colitis, GVHD and EAE (10,(32)(33)(34)36). We further show that human Tregs engage this pathway even in the absence of exogenously provided TNFa.…”

“…In mouse models of type 1 diabetes, Tregs isolated from inflamed islets, but not those from lymphoid organs, are able to suppress anti-islet autoimmune attacks (9). Similarly, in a mouse model of multiple sclerosis, Tregs in the central nervous system (CNS) are critical for limiting pathology at the peak of disease and this tissue-restricted function of Tregs depends on TNF receptor 2 (TNFR2) signaling (10). In a mouse model of islet transplant, it was reported that Tregs first traffic to the inflamed graft to suppress alloimmune responses and subsequently retreat to draining lymph nodes to maintain tolerance (11).…”

“…Conditional inactivation of TNFR2 in Tregs leads to reduced expression of Foxp3, CD25, cytotoxic T-lymphocyteassociated protein 4 and Glucocorticoid-induced tumor necrosis factor receptor and exacerbates experimental autoimmune encephalitis (EAE) (33). TNFR2-expressing Tregs are critical to suppressing EAE by limiting T cell activation in the CNS during overt inflammation (10). In addition, TNFR2 expression defines a maximally suppressive subset of Tregs that accumulates intratumorally in a Lewis lung carcinoma model (34).…”

Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation

“…The use of selective inhibition of TNF-R2 with a soluble TNF-R2 fusion protein (etanercept) has also been associated with the manifestation of MS-like demyelinating lesions due to the blockade of both sTNF and mTNF, confirming the idea that mTNF probably has a dominant role in the regenerative process and resolution of inflammation [ 33 ]. It has been recently suggested that the protective function in inflamed central nervous system pathology by T regulatory cells requires the surface expression of TNF-R2, therefore explaining the potential of some adverse effects of anti-TNF therapy in patients [ 34 ].…”

Phenotypic and Functional Diversity in Regulatory T Cells

“…This was due to constitutive expression of BLIMP1 in a STAT1-dependent manner, which antagonized IL-6-directed methylation of key regulatory regions of the Foxp3 locus. BLIMP1 expression, in turn, has been shown to be maintained by stimulation of the tumor necrosis factor receptor 2 (TNFR2), which is highly expressed in CNS Tregs ( Ronin et al, 2021 ). This is consistent with separate work demonstrating the importance of TNFRSF members at inducing and maintaining effector Tregs, in an NF-kB dependent manner ( Vasanthakumar et al, 2017 ).…”