Binding of phosphatidyl-inositol-3-OH kinase to CD28 is required for T-cell signalling (original) (raw)

Nature volume 369, pages 327–329 (1994) Cite this article

A Correction to this article was published on 14 July 1994

Abstract

THE engagement of CD28 with its ligand B7.1/CD80 results in potent costimulation of T-cell activation initiated through the CD3/T-cell receptor complex1,2. The biochemical basis of CD28 costimulatory function is poorly understood. The signalling pathways used by CD28 are unlike those used by the CD3/T-cell receptor in that they are resistant to cyclosporin A and independent of changes in cyclic AMP concentrations3. These differences suggest that each pathway provides unique biochemical informa-tion which is required for T-cell activation. We report here that CD28 becomes tyrosine-phosphorylated following interaction with B7.1/CD80, which induces formation of a complex with phospha-tidylinositol-3-OH kinase, mediated by the SH2 domains of the p85 subunit of the kinase. Phosphatidylinositol-3-OH kinase is a heterodimer of this 85K regulatory subunit and a 11 OK catalytic subunit, and is a common substrate for most receptor tyrosine kinases and some cytokine receptors4,5, binding through its SH2 domain to phosphotyrosine in the motif Tyr-X-X-Met in the CD28 sequence, which is highly conserved between human, mouse and rat6–8 and lies in the intracellular domain. We show that CD28 mutants that have their kinase-binding site deleted or the tyrosine at position 173 substituted by phenylalanine do not associate with the kinase after CD28 stimulation and cannot stimulate production of interleukin-2. Our results suggest that phosphatidylinositol-3-OH kinase is critical for signalling by CD28.

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Author information

Author notes

  1. Robert Rottapel
    Present address: Wellesley Hospital Research Institute, Toronto, Ontario, M4Y 1J3, Canada

Authors and Affiliations

  1. INSERM U119, 27 Bd Lei Roure, 13009, Marseille, France
    Françoise Pagès, Marguerite Ragueneau, Robert Rottapel, Jacques Nunes, Jean Imbert & Daniel Olive
  2. Smith Kline Beecham Pharmaceuticals, King of Prussia, 709 Swedeland Road, Pennsylvania, 19406, USA
    Alemseged Truneh

Authors

  1. Françoise Pagès
  2. Marguerite Ragueneau
  3. Robert Rottapel
  4. Alemseged Truneh
  5. Jacques Nunes
  6. Jean Imbert
  7. Daniel Olive

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Pagès, F., Ragueneau, M., Rottapel, R. et al. Binding of phosphatidyl-inositol-3-OH kinase to CD28 is required for T-cell signalling.Nature 369, 327–329 (1994). https://doi.org/10.1038/369327a0

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