Treg activation defect in type 1 diabetes: correction with TNFR2 agonism. Issue 1 (8th January 2016)

• Record Type: Journal Article
• Authors: Okubo, Yoshiaki; Torrey, Heather; Butterworth, John; Zheng, Hui; Faustman, Denise L
• Is Part Of: Clinical & translational immunology. Volume 5:Issue 1 (2016)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-01-08
• Subjects: Immunologic diseases -- Periodicals; Immunology -- Periodicals; Clinical medicine -- Periodicals; Immune System Diseases -- therapy; Immunotherapy; Immunologic Factors -- therapeutic use; Translational Medical Research; Molecular Targeted Therapy; Clinical medicine; Immunologic diseases; Immunology; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.079
• DOI: 10.1038/cti.2015.43
• Languages: English
• ISSNs: 2050-0068

Abstract

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. Autoimmunity: Waking up the regulators: A defect that prevents proper regulation of the immune system in type 1 diabetes can potentially be reversed via therapeutic interventions. This disease results in the destruction of pancreatic islet cells, which regulate blood glucose, by overactive immune cells. These immune cells are normally kept in check by regulatory T (Treg ) cells. A team led by Denise Faustman at Massachusetts General Hospital recently explored how this regulation fails. They showed that in type 1 diabetes appropriate numbers of Treg cells are present, but primarily exist in a relatively inactive state. This low level of activation correlates with impaired pancreatic activity and glucose control. However, the researchers found they could biochemically stimulate the Treg cells with the TNF receptor 2 (TNFR2) to restrain the destructive immune cells. Drugs that replicate this effect could offer effective treatment for this still incurable autoimmune disease.