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Epitope-Dependent Inhibition of T Cell Activation by the Ea Transgene: An Explanation for Transgene-Mediated Protection from Murine Lupus¹

Eduardo Martinez-Soría^2,*, Nabila Ibnou-Zekri^2,*, Masahiro Iwamoto^*, Marie-Laure Santiago-Raber^*, Shuichi Kikuchi^*, Marie Kosco-Vilbois and Shozo Izui^3,*

^* Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland; and NovImmune, Geneva, Switzerland

A high level expression of the Ea^d transgene encoding the I-E -chain is highly effective in the suppression of lupus autoantibody production in mice. To explore the possible modulation of the Ag-presenting capacity of B cells as a result of the transgene expression, we assessed the ability of the transgenic B cells to activate Ag-specific T cells in vitro. By using four different model Ag-MHC class II combinations, this analysis revealed that a high transgene expression in B cells markedly inhibits the activation of T cells in an epitope-dependent manner, without modulation of the I-E expression. The transgene-mediated suppression of T cell responses is likely to be related to the relative affinity of peptides derived from transgenic I-E -chains (E peptides) vs antigenic peptides to individual class II molecules. Our results support a model of autoimmunity prevention based on competition for Ag presentation, in which the generation of large amounts of E peptides with high affinity to I-A molecules decreases the use of I-A for presentation of pathogenic self-peptides by B cells, thereby preventing excessive activation of autoreactive T and B cells.

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