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Transcriptional Analysis of Clonal Deletion In Vivo¹

Center for Immunology, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

Engagement of the TCR on CD4⁺CD8⁺ thymocytes initiates either a program of survival and differentiation (positive selection) or death (clonal deletion), which is dictated in large part by the affinity of the TCR for self-peptide-MHC complexes. Although much is known about the factors involved in positive selection, little is understood about the molecular mechanism leading to clonal deletion. To gain further insight into this process, we used a highly physiological TCR transgenic mouse model to compare gene expression changes under conditions of nonselection, positive selection, and negative selection. We identified 388 genes that were differentially regulated in negative selection compared with either nonselection or positive selection. These regulated genes fall into many functional categories including cell surface and intracellular signal transduction, survival and apoptosis, transcription and translation, and adhesion and migration. Additionally, we have compared our transcriptional profile to profiles of negative selection in other model systems in an effort to identify those genes with a higher probability of being functionally relevant. These included three up-regulated genes, bim, nur77, and ian1, and one down-regulated gene, lip1. Collectively, these data provide a framework for understanding the molecular basis of clonal deletion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grant AI-50105 (to K.A.H.) and Canadian Institutes of Health Research and Alberta Heritage Foundation for Medical Research fellowships (to T.A.B.).

² Address correspondence and reprint requests to Dr. Kristin A. Hogquist, Center for Immunology, Mayo Mail Code 334, 420 Delaware Street Southeast, Minneapolis, MN 55455. E-mail address: hogqu001{at}umn.edu

³ Abbreviations used in this paper: DP, CD4⁺CD8⁺ double positive; qRT-PCR, quantitative real-time PCR; MHC II, MHC class II; Bim, BCL2-like 11; PD-1, programmed cell death 1.

⁴ The online version of this article contains supplemental material.

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