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Consequences of Intrathymic TCR Engagement by Partial Agonist on Selection Events and Peripheral T Cell Activation Program¹

Nathalie Auphan^2,*, Anna Katharina Simon^*, Hélène Asnagli^*, Roderick J. Phillips, Mercedes Rincon^3,, Sankar Ghosh^,, Richard A. Flavell^, and Anne-Marie Schmitt-Verhulst^*

^* Centre d’Immunologie de l’Institut National de la Santé et de la Recherche Médicale et du Centre National de la Recherche Scientifique (INSERM-CNRS) de Marseille-Luminy, Marseille, France; and Section of Immunobiology and Howard Hughes Medical Institute, Yale University School of Medecine, New Haven, CT 06517

Functions elicited from mature T cells depend on the nature of the Ag. Thus, an agonist induces a larger set of cytokine responses than a partial agonist. Additionally, Ags present in the thymus influence both the selection of TCRs generated by gene rearrangement and the potential functional program of developing thymocytes. This can be approached by analysing the development of T cells in mice expressing the same transgenic TCR (tgTCR) under different conditions of intrathymic selection. H-2K^bm8 was found to act as a partial agonist for CD8⁺ T cells expressing a tgTCR specific for the H-2K^b alloantigen. Intrathymic exposure to full or to partial agonist affected the development of thymocytes at different stages, consistent with the respective CD8-independent and -dependent characteristic of the tgTCR/Ag interaction. The presence of the partial agonist led to the accumulation of a major population of thymocytes (tgTCR^highCD4^-CD8^low) originating from TCR engagement at the immature single-positive CD8^low stage as evidenced by: 1) results from reaggregated thymic organ culture in the presence of H-2^k/bm8 thymic stromal cells; 2) the absence of CD4⁺ thymocytes, the development of which depends on rearrangements of endogenous TCR genes; and 3) the identification of the CD8^low thymocytes as cycling cells. Peripheral CD8^low T cells selected in an H-2^k/bm8 thymus expressed a partial functional program in response to H-2K^b, akin to the response of CD8^high T cells to a partial agonist. The analysis of the molecular bases for partial reactivity revealed a correlation with inefficient AP-1, but efficient NF-B transactivation.

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