Liston, AdrianHardy, KristinePittelkow, YvonneWilson, Susan RMakaroff, Lydia EFahrer, Aude MGoodnow, Christopher C2015-09-042015-09-041465-6906http://hdl.handle.net/1885/15201BACKGROUND T cells in the thymus undergo opposing positive and negative selection processes so that the only T cells entering circulation are those bearing a T cell receptor (TCR) with a low affinity for self. The mechanism differentiating negative from positive selection is poorly understood, despite the fact that inherited defects in negative selection underlie organ-specific autoimmune disease in AIRE-deficient people and the non-obese diabetic (NOD) mouse strain RESULTS Here we use homogeneous populations of T cells undergoing either positive or negative selection in vivo together with genome-wide transcription profiling on microarrays to identify the gene expression differences underlying negative selection to an Aire-dependent organ-specific antigen, including the upregulation of a genomic cluster in the cytogenetic band 2F. Analysis of defective negative selection in the autoimmune-prone NOD strain demonstrates a global impairment in the induction of the negative selection response gene set, but little difference in positive selection response genes. Combining expression differences with genetic linkage data, we identify differentially expressed candidate genes, including Bim, Bnip3, Smox, Pdrg1, Id1, Pdcd1, Ly6c, Pdia3, Trim30 and Trim12. CONCLUSION The data provide a molecular map of the negative selection response in vivo and, by analysis of deviations from this pathway in the autoimmune susceptible NOD strain, suggest that susceptibility arises from small expression differences in genes acting at multiple points in the pathway between the TCR and cell death.This work was supported by grants from the NHMRC and the Juvenile Diabetes Research Foundation.Copyright © 2007 Liston et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.allelesanimalscell differentiationdiabetes mellitusfemalegene expression regulationgenetic linkagegenomemicemice, inbred nodmice, mutant strainsorgan specificityrna, messengert-lymphocytesthymus glandgene expression profilinggenetic predisposition to diseasegenomicsselection, genetic200710.1186/gb-2007-8-1-r122016-02-24