Open AccessTreg activation defect in type 1 diabetes: correction with TNFR2 agonism
Author(s) -
Okubo Yoshiaki,
Torrey Heather,
Butterworth John,
Zheng Hui,
Faustman Denise L
Publication year - 2016
Publication title -
clinical and translational immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.321
H-Index - 34
ISSN - 2050-0068
DOI - 10.1038/cti.2015.43
Subject(s) - foxp3 , il 2 receptor , autoimmunity , tumor necrosis factor alpha , agonist , receptor , medicine , endocrinology , immunology , chemistry , immune system , t cell
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.