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Beta-catenin signaling mediates CD4 expression on mature CD8+ T cells

Jason M Schenkel1, Andrew Zloza, Wei Li

  • 1Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612, USA.

Journal of Immunology (Baltimore, Md. : 1950)
|July 16, 2010
PubMed

Insights

Mature CD8(+) T cells can re-express CD4, forming a CD4(dim)CD8(bright) population crucial for antiviral responses. Beta-catenin signaling drives this CD4 upregulation, suggesting a shared pathway with thymocyte development.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Signaling

Background:

  • A subset of mature human CD8(+) T cells re-expresses CD4 upon activation, forming a CD4(dim)CD8(bright) population enriched in antiviral responses.
  • The precise signaling pathway governing CD4 re-expression on mature CD8(+) T cells remains unclear.
  • Wnt/beta-catenin signaling is known to be vital for the CD4(+)CD8(+) thymocyte stage.

Purpose of the Study:

  • To investigate whether beta-catenin signaling mediates CD4 expression on mature CD8(+) T cells.
  • To elucidate the role of beta-catenin in the CD4(dim)CD8(bright) T cell population.

Main Methods:

  • Quantification of active beta-catenin in CD4(dim)CD8(bright) versus CD4(-)CD8(+) T cells.
  • Manipulation of beta-catenin signaling using LiCl, constitutively active beta-catenin constructs, and dominant-negative T cell factor-4 constructs.
  • Analysis of CD4 mRNA levels and identification of transcription factor binding sites in the human CD4 promoter.
  • Assessment of antiapoptotic factor BcL-xL expression.

Main Results:

  • Active beta-catenin expression was significantly higher (20-fold) in CD4(dim)CD8(bright) T cells compared to CD4(-)CD8(+) T cells.
  • Activation of beta-catenin signaling increased CD4 expression on CD8(+) T cells by approximately 10-fold.
  • Inhibition of beta-catenin signaling reduced CD4 expression by 50% upon T cell activation.
  • Beta-catenin mediated CD4 upregulation transcriptionally, increasing CD4 mRNA and interacting with T cell factor/lymphoid enhancer factor sites.
  • Beta-catenin expression also induced the antiapoptotic factor BcL-xL.

Conclusions:

  • Beta-catenin signaling is critical for inducing CD4 expression on mature CD8(+) T cells.
  • This pathway appears to be a common mechanism for CD4 upregulation in both thymocytes and mature CD8(+) T cells.
  • Beta-catenin may also confer protection against activation-induced cell death in CD8(+) T cells via BcL-xL induction.

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