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Disruption of T cell signaling networks and development by Grb2 haploid insufficiency

Nature Immunology volume 2, pages 29–36 (2001)Cite this article

Abstract

The developmental processes of positive and negative selection in the thymus shape the T cell antigen receptor (TCR) repertoire and require the integration of multiple signaling networks. These networks involve the efficient assembly of macromolecular complexes and are mediated by multimodular adaptor proteins that permit the functional integration of distinct signaling molecules. We show here that decreased expression of the adaptor protein Grb2 in Grb2 +/− mice weakens TCR-induced c-Jun N-terminal kinase (JNK) and p38, but not extracellular signal–regulated kinase (ERK), activation. In turn, this selective effect decreases the ability of thymocytes to undergo negative, but not positive, selection. We also show that there are differences in the signaling thresholds of the three mitogen-activated protein kinase (MAPK) families. These differences may provide a mechanism by which quantitative differences in signal strength can alter the balance of downstream signaling pathways to induce the qualitatively distinct biological outcomes of proliferation, differentiation or apoptosis.

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Figure 1: Decreased Grb2 expression and normal ERK activation in Grb2+/− mice.
Figure 2: Attenuated JNK and p38 activation in Grb2+/− thymocytes.
Figure 3: Normal positive selection in Grb2+/− mice.
Figure 4: Haploid insufficiency effect of Grb2 on negative selection.
Figure 5: Decreased Ras activation and normal calcium increases in Grb2+/− mice.
Figure 6: Distinct thresholds for activation of MAPKs.
Figure 7: Inhibition of ERK but not of JNK activation in mice that express Ras(N17).
Figure 8: Relationship between signal strength, MAPK activation and biological outcome.

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Acknowledgements

We thank K. Blumer, H. Piwnica-Worms, T. Chatila, A. Shaw and P. Allen for critical reading of the manuscript and A. Weiss and R. Germain for critical discussion of the data. Supported, in part, by the National Institutes of Health (grant number AI47330), the Medical Research Council of Canada (to T. P.) and a Terry Fox Program Project Grant from the National Cancer Institute of Canada (to T. P.). T. P. is a Distinguished Scientist of the Medical Research Council.

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, 63110, MO, USA

    Qian Gong & Andrew C. Chan

  2. Division of Rheumatology, Departments of Medicine and Pathology, Center for Immunology, Washington University School of Medicine, St. Louis, 63110, MO, USA

    Alec M. Cheng, Antonina M. Akk & Guoqing Gong

  3. Division of Biology, California Institute of Technology, Pasadena, 91125, CA, USA

    Jose Alberola-Ila

  4. Samuel Lunenfeld Research Institute, Mount Sinai Hospital , Toronto, M5G1X5, ON, Canada

    Tony Pawson

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Correspondence to Andrew C. Chan.

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Gong, Q., Cheng, A., Akk, A. et al. Disruption of T cell signaling networks and development by Grb2 haploid insufficiency. Nat Immunol 2, 29–36 (2001). https://doi.org/10.1038/83134

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