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/β from CD3 Signaling



Department of Immunology, University of Toronto, and The Arthritis and Immune Disorder Research Center, Toronto, Ontario, Canada M5G 2M9; the
Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida 33101; the || McGill Cancer Centre and the Departments of Biochemistry, Medicine, and Oncology, McGill University, Montreal, Quebec, Canada H3G 1Y6; and the ¶ Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois 60637
T cell activation and clonal expansion is the result of the coordinated functions of the receptors for antigen and interleukin (IL)-2. The protein tyrosine kinase p56lck is critical for the generation of signals emanating from the T cell antigen receptor (TCR) and has also been demonstrated to play a role in IL-2 receptor signaling. We demonstrate that an IL-2–dependent, antigen-specific CD4+ T cell clone is not responsive to anti-TCR induced growth when propagated in IL-2, but remains responsive to both antigen and CD3
-specific monoclonal antibody. Survival of this IL-2–dependent clone in the absence of IL-2 was supported by overexpression of exogenous Bcl-xL. Culture of this clonal variant in the absence of IL-2 rendered it susceptible to anti-TCR–induced signaling, and correlated with the presence of kinase-active Lck associated with the plasma membrane. The same phenotype is observed in primary, resting CD4+ T cells. Furthermore, the presence of kinase active Lck associated with the plasma membrane correlates with the presence of ZAP 70–pp21
complexes in both primary T cells and T cell clones in circumstances of responsive anti-TCR signaling. The results presented demonstrate that IL-2 signal transduction results in the functional uncoupling of the TCR complex through altering the subcellular distribution of kinase-active Lck.
Key Words: Lck kinase interleukin 2 regulation
L. Haughn was supported by a fellowship from the Cancer Research Society, Inc. B. Leung was supported by a Medical Research Council studentship. A. Veillette is the recipient of an MRC Scientist Award. This work was supported by grants from the Medical Research Council of Canada, the National Cancer Institute, and the National Institutes of Health.
L. Haughn and B. Leung contributed equally to this paper.
Abbreviations used: HMF, heavy membrane fraction; HRP, horseradish peroxidase.
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