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Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines

Nature Immunology volume 2, pages 37–44 (2001)Cite this article

Abstract

A region of the interleukin-2 (IL-2) promoter known as the RE/AP element is activated in concert by signals that originate from the T cell antigen receptor and the CD28 coreceptor. We show here that the serine-threonine kinase Akt can provide a costimulatory signal for RE/AP activation that is indistinguishable from the signal provided by CD28. This includes the ability of Akt, like antibodies to CD28, to synergize with protein kinase C θ (PKC-θ) in the induction of RE/AP. Retrovirus-mediated expression of activated Akt in primary T cells from CD28-deficient mice is capable of selectively restoring production of IL-2 and interferon γ, but not IL-4 or IL-5. Our results provide evidence that CD28 costimulation of different cytokines is mediated by discrete signaling pathways, one of which includes Akt.

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Figure 1: Costimulation of the IL-2 promoter and RE/AP by Akt.
Figure 2: Akt can replace the CD28 costimulatory signal for RE/AP induction by superantigen stimulation.
Figure 3: Inducible phosphorylation of Akt after CD28 ligation.
Figure 4: Akt costimulation resembles that provided by CD28.
Figure 5: Inhibition of IL-2 production in primary T cells by LY294002.
Figure 6: Expression of retrovirally encoded active Akt in primary T cells and effect on proliferation.
Figure 7: Akt substitutes for CD28 in IL-2 and IFN-γ production by primary T cells.
Figure 8

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Acknowledgements

We thank R. Locksley and C. McArthur for use of the MoFlo sorter and expert flow cytometry, respectively. Supported by the Cancer Research Institute (L. P. K.), the Glaxo Wellcome Institute for Digestive Health (P. G. A.) and National Institutes of Health grants AI25022 and AI35297 (A. K. A.).

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Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, 94143, CA, USA

    Lawrence P. Kane & Arthur Weiss

  2. Division of Gastroenterology, University of California, San Francisco, 94143, CA, USA

    Pietro G. Andres

  3. Division of Rheumatology, University of California, San Francisco, 94143, CA, USA

    Arthur Weiss

  4. Department of Pathology, University of California, San Francisco, 94143, CA, USA

    Kimberly C. Howland & Abul K. Abbas

  5. The Howard Hughes Medical Institute, University of California, San Francisco, 94143, CA, USA

    Arthur Weiss

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Kane, L., Andres, P., Howland, K. et al. Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-γ but not TH2 cytokines. Nat Immunol 2, 37–44 (2001). https://doi.org/10.1038/83144

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