Autoimmune Diabetes Onset Results From Qualitative Rather Than Quantitative Age-Dependent Changes in Pathogenic T-Cells

Abstract

Diabetogenic T-cells can be detected in pre-diabetic nonobese diabetic (NOD) mice after transfer in NOD-SCID recipients. Here we demonstrate that 6-week-old pre-diabetic NOD mice, >2 months before disease onset, already harbor pathogenic T-cells in equal numbers to overtly diabetic animals. The delay in diabetes appearance is explained by the presence of regulatory CD4 ؉ CD25؉ T-cells that control diabetogenic effectors and that are, in our hands, transforming growth factor (TGF)-␤-dependent. Our present results suggest, however, that diabetes onset is only partly explained by a decline in this regulatory T-cell activity. Another major factor appears to be the progressive resistance of diabetogenic cells to TGF-␤-dependent mediated inhibition. We propose that progression to overt disease correlates with the pathogenic T-cell's escape from TGF-␤-dependent T-cell-mediated regulation.

Diabetes in non‐obese diabetic mice is not associated with quantitative changes in CD4+ CD25+ Foxp3+ regulatory T cells

“…Evidence in favour of this argument comes from recent observations that 6-week-old but not 4-week-old NOD splenocytes depleted of CD25 + and CD62L + cells are able to transfer disease to NOD.scid mice, suggesting a temporal change in the diabetogenic capacity of NOD effector cells. 30 This is further supported by our own observations that CD25-depleted splenocytes from 14-week-old nondiabetic NOD mice are able to transfer diabetes more rapidly in NOD.scid mice than CD25 + -depleted splenocytes from 7-week-old NOD mice (data not shown).…”

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

“…Second, decreased suppressive function [53,54] and lower numbers of Treg [55,56] are considered as mechanisms that contribute to the evolution of insulitis in NOD mice. Although such a decline in Treg has been not observed in other studies [51,52], concurrent elimination of pathogenic cells has the distinct advantage of direct repression of the autoimmune process. Third, FOXP3 + T cells in the pancreas and draining lymphatics are less sensitive to apoptosis induced by IL2-cas, resulting in expansion of C25 − FOXP3 + cells.…”

“…First, direct introduction of toxic moieties through the IL-2/ IL-2 receptor complex overcomes the relative resistance of NOD lymphocytes to apoptosis (as compared with wildtype mice) [49,50], and the decreased susceptibility of diabetogenic cells to Treg-mediated inhibition [33,51,52]. Inasmuch as B cell lymphoma protein 2 (BCL-2) is associated with the survival of islet-infiltrating T cells [18], IL2-cas was found to reduce the BCL-2/apoptosis regulator BAX ratio in a model of toxic colitis [25], suggesting that the fusion protein sensitises pathogenic lymphocytes to apoptosis.…”

Increased thymic development of regulatory T cells in NOD mice is functionally dissociated from type I diabetes susceptibility

“…Treg cells can prevent diabetes and even reverse established pathology in non-obese diabetic (NOD) mice [2][3][4]. Interestingly, an age-dependent decline in the in vitro and in vivo function of NOD CD4 + CD25 + Treg cells was reported [5,6]. This conclusion * These authors contributed equally to this work.…”

“…One of was challenged and it was suggested that the decline may reflect contamination of the CD4 + CD25 + "Treg" cells with Foxp3 − cells that lack regulatory capacity [7]. However, control of diabetogenic T-cell activity may still be defective since conventional T (Tconv) cells from older NOD mice were found to be relatively resistant to suppression by Treg cells [5,6,8]. Importantly, a recent study showed that the TCR-repertoire of Treg cells may be less diverse in NOD than in B6 mice [9].…”