Thymic negative selection is functional in NOD mice.

The Journal of Experimental Medicine
Michael MingueneauChristophe Benoist

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 αβ/γδ-lineage decisions promoted by early expression of tg αβ-TCRs at the double-negative (DN) stage. In B6 and other genetic backgrounds, tg αβ-TCRs behave like γδ-TCRs and commit a large fraction of DNs toward the γδ-lineage, thereby decreasing the size of the double-positive (DP) pool, which is efficiently positively and negatively selected. In NOD DNs, αβ-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 αβ-TCR signalosomes. Therefore, NOD genetic ...Continue Reading

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May 7, 2013·Nature Immunology·Michael MingueneauShannon Turley
Nov 2, 2014·Proceedings of the National Academy of Sciences of the United States of America·Michael MingueneauChristophe Benoist
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Methods Mentioned

BETA
transgenic
dissection
flow cytometry
PMA
PCR
chips
flow cytometry gating

Software Mentioned

FlowJo
ImmGen
Affymetrix
Expression File Creator
GenePattern

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