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Direct Recognition of Foreign MHC Determinants by Naive T Cells Mobilizes Specific V Families Without Skewing of the Complementarity-Determining Region 3 Length Distribution¹

Fabien Sebille^*, Katia Gagne^*, Marina Guillet^*, Nicolas Degauque^*, Annaïck Pallier^*, Sophie Brouard^*, Bernard Vanhove^*, Marc-André Delsuc and Jean-Paul Soulillou^*

^* Institut National de la Santé et de la Recherche Medicale, Unité 437, "Immunointervention dans les Allo et Xenotransplantations" and Institut de Transplantation et de Recherche en Transplantation, Nantes, France; and Faculte de Pharmacie, Centre de Biochimie Structurale, Montpellier, France 4. M. Guillet, S. Brouard, K. Gagne, F. Sebille, M.-C. Cuturi, M.-A. Delsuc, and J.-P. Soulillou. Different qualitative and quantitative regulation of V TCR transcripts during early acute allograft rejection and tolerance induction: absence of CDR3 selection during acute rejection. Submitted for publication.

The capacity of T cells to interact with nonself-APC, also referred to as direct allorecognition, is an essential feature of the cellular response involved in graft rejection. However, there is no study on TCR repertoire biases associated with direct restricted T cell activation. In this paper, we have addressed the impact of direct recognition on the whole naive T cell repertoire, using a new approach that provides, for the first time, an integrated depiction of the quantitative and qualitative alterations in the TCR V transcriptome. This method can differentiate resting patterns from polyclonally activated ones, as evidenced by superantigen usage. According to this new readout, we show that direct recognition of nonself-MHC molecules triggers mRNA accumulation of several TCR V families, specific to the combination studied. Moreover, in marked contrast to the situation that prevails in indirect allorecognition, T cell activation through the direct presentation pathway was not associated with skewing of the complementarity determining region (CDR) 3 length distribution. Altogether, these data argue for the significance of TCR contacts with the MHC framework in direct allorecognition. In addition, the TCR diversity mobilized by this interaction and the massive TCR mRNA accumulation observed after a few days of culture suggest that a significant proportion of naive T cells receive a signal leading to TCR transcriptional activation even though only a few of them engage in mitosis.

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