J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/07/221/08 $2.00
Volume 186, Number 2, July 21, 1997 221-228

Itk Negatively Regulates Induction of  T Cell Proliferation by CD28 Costimulation

By X. Charlene Liao,^*§ Sylvie Fournier, Nigel Killeen,^* Arthur Weiss,^*§ James P. Allison, and Dan R. Littman^*

From the ^* Department of Microbiology and Immunology, University of California, San Francisco, California 94143;  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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Khurana, D., Arneson, L. N., Schoon, R. A., Dick, C. J., Leibson, P. J. (2007). Differential Regulation of Human NK Cell-Mediated Cytotoxicity by the Tyrosine Kinase Itk. J. Immunol. 178: 3575-3582 [Abstract] [Full Text]  
• Li, C.-R., Berg, L. J. (2005). Cutting Edge: Itk Is Not Essential for CD28 Signaling in Naive T Cells. J. Immunol. 174: 4475-4479 [Abstract] [Full Text]  
• Tavano, R., Gri, G., Molon, B., Marinari, B., Rudd, C. E., Tuosto, L., Viola, A. (2004). CD28 and Lipid Rafts Coordinate Recruitment of Lck to the Immunological Synapse of Human T Lymphocytes. J. Immunol. 173: 5392-5397 [Abstract] [Full Text]  
• Deane, J. A., Trifilo, M. J., Yballe, C. M., Choi, S., Lane, T. E., Fruman, D. A. (2004). Enhanced T Cell Proliferation in Mice Lacking the p85{beta} Subunit of Phosphoinositide 3-Kinase. J. Immunol. 172: 6615-6625 [Abstract] [Full Text]  
• Mueller, C., August, A. (2003). Attenuation of Immunological Symptoms of Allergic Asthma in Mice Lacking the Tyrosine Kinase ITK. J. Immunol. 170: 5056-5063 [Abstract] [Full Text]  
• Cook, J. A., August, A., Henderson, A. J. (2002). Recruitment of Phosphatidylinositol 3-Kinase to CD28 Inhibits HIV Transcription by a Tat-Dependent Mechanism. J. Immunol. 169: 254-260 [Abstract] [Full Text]  
• Miller, A. T., Berg, L. J. (2002). Defective Fas Ligand Expression and Activation-Induced Cell Death in the Absence of IL-2-Inducible T Cell Kinase. J. Immunol. 168: 2163-2172 [Abstract] [Full Text]  
• Kovalev, G. I., Franklin, D. S., Coffield, V. M., Xiong, Y., Su, L. (2001). An Important Role of CDK Inhibitor p18INK4c in Modulating Antigen Receptor-Mediated T Cell Proliferation. J. Immunol. 167: 3285-3292 [Abstract] [Full Text]  
• Ellmeier, W., Jung, S., Sunshine, M. J., Hatam, F., Xu, Y., Baltimore, D., Mano, H., Littman, D. R. (2000). Severe B Cell Deficiency in Mice Lacking the Tec Kinase Family Members Tec and Btk. JEM 192: 1611-1624 [Abstract] [Full Text]  
• Schneider, H., Guerette, B., Guntermann, C., Rudd, C. E. (2000). Resting Lymphocyte Kinase (Rlk/Txk) Targets Lymphoid Adaptor SLP-76 in the Cooperative Activation of Interleukin-2 Transcription in T-cells. J. Biol. Chem. 275: 3835-3840 [Abstract] [Full Text]  
• Rajagopal, K., Sommers, C. L., Decker, D. C., Mitchell, E. O., Korthauer, U., Sperling, A. I., Kozak, C. A., Love, P. E., Bluestone, J. A. (1999). RIBP, a Novel Rlk/Txk- and Itk-binding Adaptor Protein That Regulates T Cell Activation. JEM 190: 1657-1668 [Abstract] [Full Text]  
• Sommers, C. L., Rabin, R. L., Grinberg, A., Tsay, H. C., Farber, J., Love, P. E. (1999). A Role for the Tec Family Tyrosine Kinase Txk in T Cell Activation and Thymocyte Selection. JEM 190: 1427-1438 [Abstract] [Full Text]  
• Kempiak, S. J., Hiura, T. S., Nel, A. E. (1999). The Jun Kinase Cascade Is Responsible for Activating the CD28 Response Element of the IL-2 Promoter: Proof of Cross-Talk with the I{kappa}B Kinase Cascade. J. Immunol. 162: 3176-3187 [Abstract] [Full Text]  
• Tsuchida, M., Knechtle, S. J., Hamawy, M. M. (1999). CD28 Ligation Induces Tyrosine Phosphorylation of Pyk2 but Not Fak in Jurkat T Cells. J. Biol. Chem. 274: 6735-6740 [Abstract] [Full Text]  
• Yang, W.-C., Ghiotto, M., Barbarat, B., Olive, D. (1999). The Role of Tec Protein-tyrosine Kinase in T Cell Signaling. J. Biol. Chem. 274: 607-617 [Abstract] [Full Text]  
• Lu, Y., Cuevas, B., Gibson, S., Khan, H., LaPushin, R., Imboden, J., Mills, G. B. (1998). Phosphatidylinositol 3-Kinase Is Required for CD28 But Not CD3 Regulation of the TEC Family Tyrosine Kinase EMT/ITK/TSK: Functional and Physical Interaction of EMT with Phosphatidylinositol 3-Kinase. J. Immunol. 161: 5404-5412 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS