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Published online before print May 9, 2008

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(Journal of Leukocyte Biology. 2008;84:431-439.)
© 2008 by Society for Leukocyte Biology

Disruption of the homeostatic balance between autoaggressive (CD4⁺CD40⁺) and regulatory (CD4⁺CD25⁺FoxP3⁺) T cells promotes diabetes

Webb-Waring Institute and Department of Medicine, University of Colorado Denver School of Medicine, Denver, Colorado, USA

¹ Correspondence: Webb-Waring Institute and Department of Medicine, University of Colorado Denver School of Medicine, 4200 East 9th Ave., Denver, CO 80262, USA. E-mail: david.wagner{at}uchsc.edu

ABSTRACT

Although regulatory T cells (Tregs) are well described, identifying autoaggressive effector T cells has proven more difficult. However, we identified CD4^loCD40⁺ (Th40) cells as being necessary and sufficient for diabetes in the NOD mouse model. Importantly, these cells are present in pancreata of prediabetic and diabetic NOD mice, and Th40 cells but not CD4⁺CD40^– T cells transfer progressive insulitis and diabetes to NOD.scid recipients. Nonobese-resistant (NOR) mice have the identical T cell developmental background as NOD mice, yet they are diabetes-resistant. The seminal issue is how NOR mice remain tolerant to diabetogenic self-antigens. We show here that autoaggressive T cells develop in NOR mice and are confined to the Th40 subset. However, NOR mice maintain Treg numbers equivalent to their Th40 numbers. NOD mice have statistically equal numbers of CD4⁺CD25⁺forkhead box P3⁺intrinsic Tregs compared with NOR or nonautoimmune BALB/c mice, and NOD Tregs are equally as suppressive as NOR Tregs. A critical difference is that NOD mice develop expanded numbers of Th40 cells. We suggest that a determinant factor for autoimmunity includes the Th40:Treg ratio. Mechanistically, NOD Th40 cells have low susceptibility to Fas-induced cell death and unlike cells from NOR and BALB/c mice, have predominantly low Fas expression. CD40 engagement of Th40 cells induces Fas expression but further confers resistance to Fas-mediated cell death in NOD mice. A second fundamental difference is that NOD Th40 cells undergo much more rapid homeostatic expansion than Th40 cells from NOR mice.

Key Words: autoimmunity • homeostasis • Treg • tolerance • diabetes