CD25high T cells with a prolonged survival inhibit development of diabetes.
The goal of this study is to examine a novel hypothesis that the progression of diabetes is partially due to the weakened survival of CD25high T cells, and prolonging survival of CD25high T cells inhibits the development of diabetes. Since CD28 co-stimulation is essential for the survival of CD4+CD25high T cells, we determined whether CD28-upregulated translationally controlled tumor protein (TCTP) prolongs the survival of CD4+CD25high regulatory T cells (Tregs) by a transgenic approach. The TCTP transgene prevents Tregs from undergoing apoptosis induced by interleukin-2 withdrawal-, dexamethasone-, cyclophosphamide-, and anti-Fas treatment in vitro. In addition, transgenic Tregs express higher levels of FOXP3 than wild-type counterparts and maintain suppressive activity, suggesting that TCTP promotes Tregs escape from thymic negative selection, and that prolonged survival does not attenuate Treg suppression. Moreover, TCTP transgenic Tregs inhibit the development of autoimmune diabetes due to increased survival of suppressive Tregs and decreased expression of pancreatic TNF-alpha. Promoting the survival of CD25high T cells leads to prolonged survival of Tregs but not activated CD25+ non-Treg T cells. Thus, we propose a new model of "two phase survival" for Tregs. Our results suggest that modulation of Treg survival can be developed as a new therapy for autoimmune diseases.
Yan
Y
Y
Department of Pharmacology and Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Xiong
Z
Z
Zhang
S
S
Song
J
J
Huang
Y
Y
Thornton
A M
AM
Wang
H
H
Yang
X-F
XF
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000517:prevention & control*; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D000090324:Tumor Protein, Translationally-Controlled 1
D053645:Interleukin-2 Receptor alpha Subunit; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1