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De Novo-Developed T Cells Have Compromised Response to Existing Alloantigens: Using L^d-Specific Transgenic 2C T Cells as Tracers in a Mouse Heart Transplantation Model¹

Hongyu Luo^2,*, Huifang Chen^*, Shijie Qi^*, Dennis Loh, Pierre Daloze^*, André Veillette^§, Dasheng Xu^* and Jiangping Wu^3,*,

^* The Louis-Charles Simard Research Center, Notre-Dame Hospital, CHUM, University of Montreal, Montreal, Canada; Department of Surgery, McGill University, Montreal, Canada; Nippon Roche Research Center, Kanagawa, Japan; and ^§ Cancer Center, McGill University, Montreal, Canada

In this study, the phenotype, TCR signaling events, and function of T cells developed de novo during adulthood in the presence of extrathymic alloantigen were investigated. C57BL/6 mice(H-2^b) were first transplanted heterotopically with BALB/c hearts (H-2^d) and treated with rapamycin for 2 wk to create a tolerant status. Three weeks postoperation, the mice were whole body irradiated and transplanted with bone marrow cells from 2C mice, which are transgenic for TCR, and most of their T cells are L^d-specific CD8 cells. The 2C T cells developed de novo in the C57BL/6 mice were not able to reject the heart allograft. No clonal deletion, TCR down-regulation, or CD8 down-regulation was found in the tolerized 2C T cells. There was no characteristic phenotype of these cells in terms of CD25, ICAM-1, CD44, and MEL-14 expression. Early TCR signaling events such as intracellular calcium concentration flux, tyrosine phosphorylation, Lck and Fyn kinase activities, and Lck and Fyn protein levels in the tolerized 2C T cells were comparable to their normal counterparts, but the tolerized T cells were defective in IL-2 production and proliferation upon H-2^d alloantigen stimulation in vitro. Exogenous IL-2 could not reverse the compromised proliferation. The results of this study indicate that during adulthood, the de novo-developed T cells become tolerant to extrathymic Ag without clonal deletion. These newly minted T cells are functionally defective although they are indistinguishable from normal T cells in phenotypes and in some early signaling events.

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