Presence of Diabetes-Inhibiting, Glutamic Acid Decarboxylase-Specific, IL-10-Dependent, Regulatory T Cells in Naive Nonobese Diabetic Mice

Abstract

Immunization of NOD mice with autoantigens such as glutamic acid decarboxylase (GAD) 221–235 peptide (p221) can induce Ag-specific CD4+ T regulatory (Tr) cells. However, it is unclear whether these Tr cells acquire their regulatory capacity due to immunization or whether they are constitutively harbored in unimmunized naive mice. To address this question, we used an I-Ag7 tetramer to isolate p221-specific T cells from naive NOD mice (N221+ cells) after peptide-specific in vitro expansion. The N221+ T cells produced IFN-γ and IL-10, but very little IL-4, in response to p221 stimulation. These T cells could function as regulatory cells and inhibit in vitro proliferation of diabetogenic BDC2.5 cells. This suppressive activity was cell contact-independent and was abrogated by Abs to IL-10 or IL-10R. Interestingly, IL-2 produced by other T cells present in the cell culture induced unactivated N221+ T cells to exhibit regulatory activities involving production of IL-10. In vivo, N221+ cells inhibited diabetes development when cotransferred with NOD splenocytes into NOD/scid recipients. Together, these results demonstrate that p221-specific IL-10-dependent Tr cells, including Tr type 1 cells, are present in naive NOD mice. The use of spontaneously arising populations of GAD peptide-specific Tr cells may represent a promising immunotherapeutic approach for preventing type 1 diabetes.

Adaptive TGF-β-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment

“…In the diabetes setting, the CD25 low T cells appear to be one of these adaptive Tregs. One may also mention that ␤-cell-specific (GAD-specific) Th2 and Tr1 cells endowed with regulatory capacities have been detected in unmanipulated NOD mice (43,44).…”

Killer cell Ig-like receptor (KIR) 3DL1 down-regulation enhances inhibition of type 1 diabetes by autoantigen-specific regulatory T cells

“…These autoantigen-specific and cytokinedependent Tregs are able to inhibit proliferation of pathogenic T cells (Tpaths) effectively (9)(10)(11)(12). Some of these Tregs required cell contact, but others did not.…”

“…We previously isolated several CD4 + Foxp3 − Tregs that are specific for glutamic acid decarboxylase (GAD), a major autoantigen in T1D (9)(10)(11)(12). These autoantigen-specific and cytokinedependent Tregs are able to inhibit proliferation of pathogenic T cells (Tpaths) effectively (9)(10)(11)(12).…”

The Role of Regulatory T Cell Defects in Type I Diabetes and the Potential of these Cells for Therapy

“…Intriguingly, it appears that in the mouse a subset of dendritic cells exist that specifically induce their differentiation [26]. Such a population of GAD-specific Tr1 cells has recently been identified in young NOD mice [27]. A role for pathogen-specific Tr1 cells has also been posited as a possible mechanism by which mammals limit potentially harmful immunopathology [28,29].…”