TNF receptor 1 deficiency increases regulatory T cell function in nonobese diabetic mice

Jonathan Chee, Eveline Angstetra, Lina Mariana, Kate L. Graham, Emma M. Carrington, Horst Bluethmann, Pere Santamaria, Janette Allison, Thomas W.H. Kay, Balasubramanian Krishnamurthy, Helen E. Thomas

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

TNF has been implicated in the pathogenesis of type 1 diabetes. When administered early in life, TNF accelerates and increases diabetes in NOD mice. However, when administered late, TNF decreases diabetes incidence and delays onset. TNFR1-deficient NOD mice were fully protected from diabetes and only showed mild peri-insulitis. To further dissect how TNFR1 deficiency affects type 1 diabetes, these mice were crossed to β cell-specific, highly diabetogenic TCR transgenic I-Ag7-restricted NOD4.1 mice and Kdrestricted NOD8.3 mice. TNFR1-deficient NOD4.1 and NOD8.3 mice were protected from diabetes and had significantly less insulitis compAred with wild type NOD4.1 and NOD8.3 controls. Diabetic NOD4.1 mice rejected TNFR1-deficient islet grafts as efficiently as control islets, confirming that TNFR1 signaling is not directly required for β cell destruction. Flow cytometric analysis showed a significant increase in the number of CD4+CD25+Foxp3 + T regulatory cells in TNFR1-deficient mice. TNFR1- deficient Tregulatory cells were functionally better at suppressing effector cells than were wild type Tregulatory cells both in vitro and in vivo. This study suggests that blocking TNF signaling may be beneficial in increasing the function of T regulatory cells and suppression of type 1 diabetes.

Original languageEnglish
Pages (from-to)1702-1712
Number of pages11
JournalJournal of Immunology
Volume187
Issue number4
DOIs
Publication statusPublished - 15 Aug 2011
Externally publishedYes

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