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Antigen-Induced Unresponsiveness Results in Altered T Cell Signaling¹

Dianne B. McKay^2,*,, Hanna Y. Irie^*, Georg Hollander, James L. M. F. Ferrara^§, Terry B. Strom^¶, YongSheng Li^¶ and Steven J. Burakoff^*

^* Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115; Renal Division and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Department of Pediatric Research, Kantonsspital, Basel, Switzerland; ^§ Department of Medicine, University of Michigan, Ann Arbor, MI 48109; and ^¶ Renal Division, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115

Pretransplant exposure to allogeneic lymphocytes can result in donor-specific unresponsiveness and prolonged allograft survival. Intracellular signaling events have been described in anergic T cell clones, but the biochemical events underlying in vivo induced unresponsiveness have not been studied in detail. We employed a TCR transgenic mouse, bearing the 2C TCR, providing adequate numbers of homogenous peripheral T cells to study biochemical aspects of T cell unresponsiveness in vivo. 2C mice exposed to semiallogeneic lymphocytes (H-2^b x H-2^d) experienced prolonged H-2^d cardiac allograft survival, and cells from these mice did not proliferate or make IL-2 in response to alloantigen (H-2^d). Importantly, there were marked differences in TCR-associated tyrosine phosphorylation activation patterns. The targets for the unresponsive state appear to be diminished Lck activation and absent ZAP-70 and LAT (linker for activation of T cells) phosphorylation. Our study demonstrates that Ag-induced tolerance in vivo is accompanied by altered early TCR-mediated signaling events.

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