Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation

doi:10.1084/jem.184.2.365

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Differential association of protein tyrosine kinases with the T cell receptor is linked to the induction of anergy and its prevention by B7 family-mediated costimulation

VA Boussiotis, DL Barber, BJ Lee, JG Gribben, GJ Freeman and LM Nadler
Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

When stimulated through their antigen receptor, without costimulation, T cells enter a state of antigen-specific unresponsiveness, termed anergy. B7-mediated costimulation, signaling via CD28, is sufficient to prevent the induction of anergy. Here we show that ligation of T cell receptor (TCR) by alloantigen alone, which results in anergy, activates tyrosine phosphorylation of TCR zeta and its association with fyn. In contrast, TCR ligation in the presence of B7 costimulation, which results in productive immunity, activates tyrosine phosphorylation of TCR zeta and CD3 chains, which associate with activated lck and zeta- associated protein (ZAP) 70. Under these conditions, CD28 associates with activated lck and TCR zeta. These data suggest that the induction of anergy is an active signaling process characterized by the association of TCR zeta and fyn. In addition, CD28-mediated costimulation may prevent the induction of anergy by facilitating the effective association of TCR zeta and CD3 epsilon with the critical protein tyrosine kinase lck, and the subsequent recruitment of ZAP-70. Strategies to inhibit or activate TCR-associated, specific protein tyrosine kinase-mediated pathways may provide a basis for drug development with potential applications in the fields of transplantation, autoimmunity, and tumor immunity.
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Ndolo, T., Dhillon, N. K., Nguyen, H., Guadalupe, M., Mudryj, M., Dandekar, S. (2002). Simian Immunodeficiency Virus Nef Protein Delays the Progression of CD4+ T Cells through G1/S Phase of the Cell Cycle. J. Virol. 76: 3587-3595 [Abstract] [Full Text]
Van Laethem, F., Baus, E., Smyth, L. A., Andris, F., Bex, F., Urbain, J., Kioussis, D., Leo, O. (2001). Glucocorticoids Attenuate T Cell Receptor Signaling. J. Exp. Med. 193: 803-814 [Abstract] [Full Text]
Utting, O., Priatel, J. J., Teh, S.-J., Teh, H.-S. (2001). p59fyn (Fyn) Promotes the Survival of Anergic CD4-CD8- {{alpha}}{{beta}} TCR+ Cells but Negatively Regulates Their Proliferative Response to Antigen Stimulation. J. Immunol. 166: 1540-1546 [Abstract] [Full Text]
Boussiotis, V. A., Chen, Z.-M., Zeller, J. C., Murphy, W. J., Berezovskaya, A., Narula, S., Roncarolo, M. G., Blazar, B. R. (2001). Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-{beta}-treated alloreactive T cells that do not induce graft-versus-host disease. Blood 97: 565-571 [Abstract] [Full Text]
Lin, H., Martelli, M. P., Bierer, B. E. (2001). The involvement of the proto-oncogene p120 c-Cbl and ZAP-70 in CD2-mediated T cell activation. Int Immunol 13: 13-22 [Abstract] [Full Text]
Huang, J., Tilly, D., Altman, A., Sugie, K., Grey, H. M. (2000). Inaugural Article: T-cell receptor antagonists induce Vav phosphorylation by selective activation of Fyn kinase. Proc. Natl. Acad. Sci. USA 97: 10923-10929 [Abstract] [Full Text]
Denny, M. F., Patai, B., Straus, D. B. (2000). Differential T-Cell Antigen Receptor Signaling Mediated by the Src Family Kinases Lck and Fyn. Mol. Cell. Biol. 20: 1426-1435 [Abstract] [Full Text]
Appleman, L. J., Berezovskaya, A., Grass, I., Boussiotis, V. A. (2000). CD28 Costimulation Mediates T Cell Expansion Via IL-2-Independent and IL-2-Dependent Regulation of Cell Cycle Progression. J. Immunol. 164: 144-151 [Abstract] [Full Text]
Raab, M., Kang, H., da Silva, A., Zhu, X., Rudd, C. E. (1999). FYN-T-FYB-SLP-76 Interactions Define a T-cell Receptor zeta /CD3-mediated Tyrosine Phosphorylation Pathway That Up-regulates Interleukin 2 Transcription in T-cells. J. Biol. Chem. 274: 21170-21179 [Abstract] [Full Text]
Salojin, K. V., Zhang, J., Delovitch, T. L. (1999). TCR and CD28 Are Coupled Via ZAP-70 to the Activation of the Vav/Rac-1-/PAK-1/p38 MAPK Signaling Pathway. J. Immunol. 163: 844-853 [Abstract] [Full Text]
GUDMUNDSDOTTIR, H., TURKA, L. A. (1999). T Cell Costimulatory Blockade: New Therapies for TransplantRejection. J. Am. Soc. Nephrol. 10: 1356-1365 [Abstract] [Full Text]
Okkenhaug, K., Rottapel, R. (1998). Grb2 Forms an Inducible Protein Complex with CD28 through a Src Homology 3�Domain-Proline Interaction. J. Biol. Chem. 273: 21194-21202 [Abstract] [Full Text]
Liu, J., Kang, H., Raab, M., da Silva, A. J., Kraeft, S.-K., Rudd, C. E. (1998). FYB (FYN binding protein) serves as a binding partner for lymphoid protein and FYN kinase substrate SKAP55 and a SKAP55-related protein in T cells. Proc. Natl. Acad. Sci. USA 95: 8779-8784 [Abstract] [Full Text]
Wong, J., Straus, D., Chan, A. C. (1998). Genetic Evidence of a Role for Lck in T-Cell Receptor Function Independent or Downstream of ZAP-70/Syk Protein Tyrosine Kinases. Mol. Cell. Biol. 18: 2855-2866 [Abstract] [Full Text]
Porcu, P., Gaddy, J., Broxmeyer, H. E. (1998). Alloantigen-induced unresponsiveness in cord blood T lymphocytes is associated with defective activation of Ras. Proc. Natl. Acad. Sci. USA 95: 4538-4543 [Abstract] [Full Text]
Fitzer-Attas, C. J., Schindler, D. G., Waks, T., Eshhar, Z. (1998). Harnessing Syk Family Tyrosine Kinases as Signaling Domains for Chimeric Single Chain of the Variable Domain Receptors: Optimal Design for T Cell Activation. J. Immunol. 160: 145-154 [Abstract] [Full Text]
Boussiotis, V. A., Freeman, G. J., Berezovskaya, A., Barber, D. L., Nadler, L. M. (1997). Maintenance of Human T Cell Anergy: Blocking of IL-2 Gene Transcription by Activated Rap1. Science 278: 124-128 [Abstract] [Full Text]
Salojin, K., Zhang, J., Cameron, M., Gill, B., Arreaza, G., Ochi, A., Delovitch, T. L. (1997). Impaired Plasma Membrane Targeting of Grb2-Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn-T Cell Receptor (TCR)-zeta -Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice. J. Exp. Med. 186: 887-897 [Abstract] [Full Text]