The Repertoire of Newly Developing Regulatory T Cells in the Type 1 Diabetes–Prone NOD Mouse Is Very Diverse

Abstract

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their in vivo activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCR and TCR variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCR and TCR chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

The type 1 diabetes susceptibility locus Idd5 favours robust neonatal development of highly autoreactive regulatory T cells in the NOD mouse

“…However, for both populations, much fewer cells proliferated in NOD than in B6 mice. It was recently shown that whereas the diversity of the TCR repertoire expressed by newly developed Tregs is similar in B6 and NOD mice (8), in peripheral lymphoid organs, this diversity is higher in NOD than in B6 mice. This phenomenon was apparently due to reduced clonal Treg expansion in NOD mice (41), which in turn is probably caused by limited production of IL-2 in NOD as compared with B6 mice (9).…”

“…Inherited defects in Treg-mediated immunoregulation may be involved in susceptibility to autoimmune diseases such as T1D. It was reported that the TCR repertoire expressed by Tregs developing in NOD mice was of limited diversity (7), but our recent highthroughput TCR-mRNA sequencing data challenged this conclusion (8). Polymorphisms in genes encoding IL-2 and its receptor components, which may affect in-vivo Treg function, are linked to diabetes in humans and mice (9)(10)(11)(12)(13).…”