Cutting edge: CD28-mediated transcriptional and posttranscriptional regulation of IL-2 expression are controlled

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Updated: Aug 14, 2026

Generation of Induced Regulatory T Cells from Primary Human Naïve and Memory T Cells
14:23

Generation of Induced Regulatory T Cells from Primary Human Naïve and Memory T Cells

Published on: April 16, 2012

Mariano Sanchez-Lockhart1, Elides Marin, Beth Graf

  • 1David H. Smith Center for Vaccine Biology and Immunology, Aab Institute, Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|December 9, 2004
PubMed

Insights

This study clarifies CD28 costimulation signaling, revealing PI3K-dependent pathways enhance IL-2 transcription via the immunological synapse. A separate PI3K-independent pathway stabilizes IL-2 mRNA, resolving long-standing PI3K role controversies.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • CD28 costimulation is crucial for T-cell activation, but its downstream signaling pathways, particularly the role of PI3K, remain debated.
  • Conflicting data has obscured the precise mechanisms by which CD28 influences immune responses.

Purpose of the Study:

  • To resolve the controversy surrounding the role of PI3K in CD28-mediated signaling.
  • To elucidate the distinct pathways through which CD28 regulates IL-2 expression.

Main Methods:

  • Site-directed mutagenesis of the PI3K interaction site in the CD28 cytosolic tail.
  • Analysis of protein recruitment to the immunological synapse (c-SMAC).
  • Assessment of NF-kappaB nuclear translocation and IL-2 gene transcription and mRNA stability.

Main Results:

  • Mutation of the PI3K interaction site on CD28 impaired recruitment of protein kinase C-theta to the c-SMAC, NF-kappaB nuclear translocation, and IL-2 gene transcription.
  • The same mutation did not affect CD28's ability to enhance IL-2 mRNA stability.
  • These findings indicate two independent pathways for CD28-induced IL-2 upregulation.

Conclusions:

  • CD28 signaling involves at least two distinct pathways: one PI3K-dependent, operating via the immunological synapse to promote IL-2 transcription, and another PI3K-independent pathway that enhances IL-2 mRNA stability.
  • This research clarifies the complex signaling network downstream of CD28, providing a more comprehensive understanding of T-cell activation.

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