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Regulation of Lck activity by CD4 and CD28 in the immunological synapse

Nature Immunology volume 3, pages 259–264 (2002)Cite this article

Abstract

Although the Src family tyrosine kinase Lck is essential for T cell receptor (TCR) signaling, whether or how Lck is activated is unknown. Using a phosphospecific antiserum to Lck, we show here that Lck becomes autophosphorylated when T cells are stimulated by antigen-presenting cells (APCs). We found that TCR cross-linking alone could not stimulate Lck autophosphorylation and CD45 was not required for this process. Instead, the T cell accessory molecules CD4 and CD28 cooperated to induce autophosphorylation of Lck. CD4 recruited Lck to the T cell–APC interface, whereas CD28 sustained Lck activation. These data show how the multiple interactions afforded by the immunological synapse drive efficient and highly specific signaling.

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Figure 1: The antiserum to pY394 is specific for autophosphorylated Lck.
Figure 2: The antiserum to pY394 has a limit of detection of ∼10 ng and only weakly reacts with autophosphorylated Fyn.
Figure 3: Autophosphorylated Lck is present at the T cell–APC interface.
Figure 4: Activation of Lck by CD4 and CD28 but not by the TCR.
Figure 5: CD4 recruits Lck to the T cell–APC interface, whereas CD28 potentiates Lck activation.

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Acknowledgements

We thank A. Chan, E. Unanue and J. Kim for critical review of the manuscript; S. Ranganath and D. Donermeyer for assistance with the T cell cultures; and J. Green for the CD28-deficient DO11.10 mice. Supported by the NIH (A. S.), the Cancer Research Institute (A. H.) and the Burroughs-Wellcome Fund (W. R. B.).

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  1. Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Campus Box 8118, St. Louis, 63110, MO, USA

    Amy D. Holdorf, Kyeong-Hee Lee, W. Richard Burack, Paul M. Allen & Andrey S. Shaw

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Holdorf, A., Lee, KH., Burack, W. et al. Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nat Immunol 3, 259–264 (2002). https://doi.org/10.1038/ni761

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