The Journal of Experimental Medicine
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Published 5 April 2004. doi:10.1084/jem.20031105
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 7, 981-991
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T Cell Receptor Engagement Leads to Phosphorylation of Clathrin Heavy Chain during Receptor Internalization

Victoria L. Crotzer1, Allan S. Mabardy1, Arthur Weiss2, and Frances M. Brodsky1,3

1 The G. W. Hooper Foundation, Department of Microbiology and Immunology, 2 Department of Medicine and The Howard Hughes Medical Institute, and 3 Department of Biopharmaceutical Sciences and Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94143

Address correspondence to Frances M. Brodsky, The G.W. Hooper Foundation, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143. Phone: (415) 476-6406; Fax: (415) 476-6185; email: fmarbro{at}itsa.ucsf.edu

T cell receptor (TCR) internalization by clathrin-coated vesicles after encounter with antigen has been implicated in the regulation of T cell responses. We demonstrate that TCR internalization after receptor engagement and TCR signaling involves inducible phosphorylation of clathrin heavy chain (CHC) in both CD4+ and CD8+ human T cells. Studies with mutant Jurkat T cells implicate the Src family kinase Lck as the responsible enzyme and its activity in this process is influenced by the functional integrity of the downstream signaling molecule ZAP-70. CHC phosphorylation positively correlates with ligand-induced TCR internalization in both CD4+ and CD8+ T cells, and CHC phosphorylation as a result of basal Lck activity is also implicated in constitutive TCR endocytosis by CD4+ T cells. Remarkably, irreversible CHC phosphorylation in the presence of pervanadate reduced both constitutive and ligand-induced TCR internalization in CD4+ T cells, and immunofluorescence studies revealed that this inhibition affected the early stages of TCR endocytosis from the plasma membrane. Thus, we propose that CHC phosphorylation and dephosphorylation are involved in TCR internalization and that this is a regulatory mechanism linking TCR signaling to endocytosis.

Key Words: T lymphocytes • endocytosis • signal transduction • Src family kinases • lymphocyte activation

Abbreviations used in this paper: BCR, B cell receptor; CCV, clathrin-coated vesicle; CHC, clathrin heavy chain; EGFR, epidermal growth factor receptor; hTfR, human transferrin receptor; ITAM, immunoreceptor tyrosine-based activating motif; LAT, linker associated with T cell activation; PTP, protein tyrosine phosphatase.


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