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Thymocyte-Intrinsic Genetic Factors Influence CD8 T Cell Lineage Commitment and Affect Selection of a Tumor-Reactive TCR¹

Anil Shanker^*, Nathalie Auphan-Anezin^*, Patrick Chomez^2,, Laurent Giraudo^*, Benoît Van den Eynde and Anne-Marie Schmitt-Verhulst^3,*

^* Centre d’Immunologie de Marseille-Luminy, and Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Universite de la Méditerranée, Marseille, France; and Ludwig Institute for Cancer Research, Brussels, Belgium

Selection of immature CD4CD8 double-positive (DP) thymocytes for CD4 or CD8-lineage commitment is controlled by the interaction of the TCR with stromal cell-expressed peptide/MHC. We show that thymocyte-intrinsic genes influence the pattern of expression of a MHC class I-restricted transgenic (tg) TCR so that in DBA/2 mice, DP thymocytes with a characteristically high expression of tg TCR, infrequently transit to CD8 single-positive thymocytes. In contrast, in B10.D2 mice, the same tg TCR is expressed at lower levels on a subpopulation of DP thymocytes that more frequently transit to CD8 single-positive thymocytes. These characteristics were not influenced by thymic stromal components that control positive selection. Radiation chimeras reconstituted with a mixture of BM from tg TCR mice of the two genetic backgrounds revealed that the relative frequency of transit to the CD8 lineage remained thymocyte-intrinsic. Identifying the gene products whose polymorphism controls CD8 T cell development may shed new light on the mechanisms controlling T cell commitment/selection in mice other than the most studied "C57BL/6"-based strains.

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