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Opposite CD4/CD8 Lineage Decisions of CD4⁺8⁺ Mouse and Rat Thymocytes to Equivalent Triggering Signals: Correlation with Thymic Expression of a Truncated CD8 Chain in Mice But Not Rats¹

Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany

Unselected CD4⁺8⁺ rat thymocytes, generated in vitro from their direct precursors, are readily converted to functional TCR^high T cells by stimulation with immobilized TCR-specific mAb plus IL-2. Lineage decision invariably occurs toward CD4^-8⁺, regardless of the timing of TCR stimulation after entry into the CD4⁺8⁺ compartment or the concentration of TCR-specific mAb used for stimulation. CD4-specific mAb synergizes with suboptimal TCR-specific mAb in inducing T cell maturation, but lineage decision remains exclusively CD4^-8⁺. These results contrast with those obtained in mice, in which Abs to the TCR complex were shown to promote CD4⁺8^- T cell maturation from CD4⁺8⁺ thymocytes. Surprisingly, when rat and mouse CD4⁺8⁺ thymocytes were stimulated with PMA/ionomycin under identical conditions, the opposite lineage commitment was observed, i.e., mouse thymocytes responded with the generation of CD4⁺8^- and rat thymocytes with the generation of CD4^-8⁺ cells. It thus seems that CD4⁺8⁺ thymocytes of the two species respond with opposite lineage decisions to strong activating signals such as given by TCR-specific mAb or PMA/ionomycin. A possible key to this difference lies in the availability of p56^lck for coreceptor-supported signaling. We show that in contrast to mouse CD4⁺8⁺ thymocytes, which express both a complete and a truncated CD8-chain (CD8') unable to bind p56^lck, rat thymocytes only express full-length CD8 molecules. Mice, but not rats, therefore may use CD8' as a "dominant negative" coreceptor chain to attenuate the CD8 signal, thereby facilitating MHC class II recognition through the higher amount of p56^lck delivered, and rats may use a different mechanism for MHC class distinction during positive selection.

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