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Lck Is Required for Activation-Induced T Cell Death after TCR Ligation with Partial Agonists¹

Xue-Zhong Yu^2,*,, Steven D. Levin^3,, Joaquin Madrenas and Claudio Anasetti^*,

^* Human Immunogenetics Program, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; Departments of Immunology and Medicine, University of Washington, Seattle, WA 98195; and Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, and the John P. Robarts Institute, London, Ontario, Canada.

TCR engagement can induce either T cell proliferation and differentiation or activation-induced T cell death (AICD) through apoptosis. The intracellular signaling pathways that dictate such a disparate fate after TCR engagement have only been partially elucidated. Non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern and cause AICD on Ag-activated, cycling T cells. In this study, we examined TCR signaling during the induction of AICD by anti-CD3 fos, a non-FcR-binding anti-CD3 mAb. This mAb activates Fyn, Lck, and extracellular signal-regulated kinase, and induces phosphorylation of Src-like adapter protein, despite the inability to cause calcium mobilization or TCR polarization. Anti-CD3 fos also fails to effectively activate -associated protein of 70 kDa or NF-B. Using Ag-specific T cells deficient for Fyn or Lck, we provide compelling evidence that activation of Lck is required for the induction of AICD. Our data indicate that a selective and distinct TCR signaling pattern is required for AICD by TCR partial agonist ligands.

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