Thymic negative selection is functional in NOD mice.

ABSTRACT: Based on analyses of multiple TCR transgenic (tg) models, the emergence of pathogenic T cells in diabetes-prone NOD mice has been ascribed to a failure to censure autoreactive clones in the thymus. In contrast, using isolated and preselected thymocytes, we show that nonobese diabetic (NOD) genetic variation impairs neither clonal deletion nor downstream transcriptional programs. However, we find that NOD genetic variation influences ??/??-lineage decisions promoted by early expression of tg ??-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg ??-TCRs behave like ??-TCRs and commit a large fraction of DNs toward the ??-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, ??-TCR signalosomes instead behave like pre-TCRs, resulting in high numbers of DPs competing for limited selection niches, and poor positive and negative selection. Once niche effects are neutralized in mixed bone marrow chimeras, positive and negative selection are equally efficient on B6 and NOD backgrounds. Biochemical analysis revealed a selective defect in the activation of Erk1/2 downstream of NOD ??-TCR signalosomes. Therefore, NOD genetic variation influences ??/??-lineage decisions when the ??-TCR heterodimer is prematurely expressed, but not the process of negative selection.

SUBMITTER: Mingueneau M 

PROVIDER: S-EPMC3302233 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature