Treg activation defect in type 1 diabetes: correction with TNFR2 agonism

Abstract

Activated T-regulatory cells (aTregs) prevent or halt various forms of autoimmunity. We show that type 1 diabetics (T1D) have a Treg activation defect through an increase in resting Tregs (rTregs, CD4+CD25+Foxp3+CD45RA) and decrease in aTregs (CD4+CD25+Foxp3+CD45RO) (n= 55 T1D, n=45 controls, P=0.01). The activation defect persists life long in T1D subjects (T1D=45, controls=45, P=0.01, P=0.04). Lower numbers of aTregs had clinical significance because they were associated with a trend for less residual C-peptide secretion from the pancreas (P=0.08), and poorer HbA1C control (P=0.03). In humans, the tumor necrosis factor receptor 2 (TNFR2) is obligatory for Treg induction, maintenance and expansion of aTregs. TNFR2 agonism is a method for stimulating Treg conversion from resting to activated. Using two separate in vitro expansion protocols, TNFR2 agonism corrected the T1D activation defect by triggering conversion of rTregs into aTregs (n=54 T1D, P<0.001). TNFR2 agonism was superior to standard protocols and TNF in proliferating Tregs. In T1D, TNFR2 agonist-expanded Tregs were homogeneous and functionally potent by virtue of suppressing autologous cytotoxic T cells in a dose-dependent manner comparable to controls. Targeting the TNFR2 receptor for Treg expansion in vitro demonstrates a means to correct the activation defect in T1D.

Control of GVHD by regulatory T cells depends on TNF produced by T cells and TNFR2 expressed by regulatory T cells

“…[12][13][14][15] This was observed in mice and humans, both in healthy individuals and type 1 diabetes patients. [16][17][18] (3) Tregs express higher levels of TNFR2 compared with Tconvs, and Tregs expressing the highest level of TNFR2 are most suppressive in mice and humans. 12,13,15 The role of TNF/TNFR2 interaction in the control of GVHD by Tregs has not been studied.…”

Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review

“…Most of the proinflammatory actions of TNF are believed to be mediated by TNF receptor-1. The roles of the TNF receptor-2, while incompletely understood [119], may include the resolution of inflammation [124,125], tissue regeneration, neuroprotection [126], and suppression of cytotoxic T-cell populations that cause type 1 diabetes mellitus [127]. Removal of serum TNF may compromise signaling through this receptor, thus abrogating these physiologic functions.…”

Can we design a better anti-cytokine therapy?

“…Finally, agonistic antibodies have been developed that enhance TNFR2 signaling and rescue human neurons from oxidative stressinduced cell death, which may, in the future, benefit patients who have TNF-mediated neurodegeneration [50]. The TNFR2 agonism approach has also been used for induction and expansion of T reg cells as correctional therapy for type 1 diabetes [51].…”