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A Physiological Ligand of Positive Selection Is Seen with High Specificity¹

Stefan Irion^*,, Rance E. Berg^*, and Uwe D. Staerz^2,*,

^* Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206; Abteilung fuer Immunologie, Interdisziplinaeres Institut fuer Zellbiologie, Eberhard-Karls-Universitaet, Tuebingen, Germany; and Cancer Center and Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262

Positive selection is a process that ensures that peripheral T cells express TCR that are restricted to self-MHC molecules. This process requires both self-MHC and self-peptides. We have recently established a TCR transgenic mouse model (C10.4 TCR_trans⁺) in which the transgenic TCR was selected on the nonclassical MHC class Ib molecule H2-M3 in conjunction with a physiologically occurring peptide derived from the mitochondrial NADH-dehydrogenase subunit 1 gene (9-mer peptide). Here, the specificity of positive selection of C10.4 TCR_trans⁺ T cells was examined using a fetal thymic organ culture system. We demonstrated that at low peptide concentrations, shortening the NADH-dehydrogenase subunit 1 gene 9-mer peptide or mutating its surface-exposed side chains severely impaired its ability to induce positive selection. We concluded that under physiological conditions positive selection of C10.4 TCR_trans⁺ T cells was highly specific and occurred at low epitope densities.

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