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© The Rockefeller University Press, 0022-1007/1997/7/221/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 2, July 21, 1997 221-228

Article

Itk Negatively Regulates Induction of T Cell Proliferation by CD28 Costimulation

X. Charlene Liao*,§, Sylvie Fournier{ddagger}, Nigel Killeen*, Arthur Weiss*,§, James P. Allison{ddagger}, and Dan R. Littman*,||

From the * Department of Microbiology and Immunology, University of California, San Francisco, California 94143; {ddagger} Department of Molecular and Cell Biology, Cancer Research Laboratory, University of California, Berkeley, California 94720; § Department of Medicine, Howard Hughes Medical Institute, University of California, San Francisco, California 94143; and the || Howard Hughes Medical Institute, The Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York 10016

CD28 is a cell surface molecule that mediates a costimulatory signal crucial for T cell proliferation and lymphokine production. The signal transduction mechanisms of CD28 are not well understood. Itk, a nonreceptor protein tyrosine kinase specifically expressed in T cells and mast cells, has been implicated in the CD28 signaling pathway because of reports that it becomes phosphorylated on tyrosines and associates with CD28 upon cross-linking of the cell surface molecule. To determine whether Itk plays a functional role in CD28 signaling, we compared T cells from Itk-deficient mice and control mice for their responses to CD28 costimulation. T cells defective in Itk were found to be fully competent to respond to costimulation. Whereas the CD3-mediated proliferative response was severely compromised in the absence of Itk, the calcineurin-independent CD28-mediated response was significantly elevated when compared with cells from control animals. The augmented proliferation was not due to increased production of interleukin-2. The results suggest that Itk has distinct roles in the CD3 versus the CD28 signaling pathways. By negatively regulating the amplitude of signaling upon CD28 costimulation, Itk may provide a means for modulating the outcome of T cell activation during development and during antigen-driven immune responses.

Address correspondence to Dan R. Littman, Howard Hughes Medical Institute, Molecular Pathogenesis Program, The Skirball Institute of Biomolecular Medicine, second floor, New York University Medical Center, 540 First Avenue, New York 10016. Phone: 212-263-7579; FAX: 212-263-5711; E-mail: Littman{at}saturn.med.nyu.edu. The current address for X.C. Liao is Tularik, Inc., Two Corporate Drive, South San Francisco, California 94080.

X.C. Liao and S. Fournier should be considered co–first authors of this study.

1Abbreviations used in this paper: CsA, cyclosporin A; IL-2R{alpha}, interleukin-2 receptor {alpha} chain; JNK, c-Jun NH2 terminus kinase; PI3K, phosphatidylinositol 3' kinase; PKC, protein kinase C; PLC{gamma}1, phospholipase C{gamma}1.


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