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SAP regulates T(H)2 differentiation and PKC-theta-mediated activation of NF-kappaB1

Jennifer L Cannons1, Li J Yu, Brenna Hill

  • 1National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Immunity
|November 13, 2004
PubMed

Insights

X-linked lymphoproliferative disease (XLP) arises from mutations in SAP, impacting T cell responses. This study reveals SAP deficiency impairs T helper 2 (T(H)2) cytokine production by disrupting T cell receptor signaling pathways.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • X-linked lymphoproliferative disease (XLP) is linked to mutations in the Signaling Adaptor Protein (SAP).
  • SAP is crucial for recruiting Fyn kinase to SLAM family receptors, influencing T cell function.
  • SAP-deficient mice exhibit XLP-like symptoms, including heightened T cell activation and diminished antibody production.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying impaired T(H)2 cytokine production in SAP-deficient T cells.
  • To elucidate the role of the SAP-Fyn pathway in T cell receptor (TCR) signaling and T(H)2 differentiation.

Main Methods:

  • Analysis of cytokine production (IFN-gamma, IL-4) in wild-type and SAP-deficient T cells.
  • Examination of TCR signaling components, including calcium mobilization, ERK activation, and PKC-theta recruitment.
  • Assessment of downstream signaling events like Bcl-10 phosphorylation, IkappaB-alpha degradation, and NF-kappaB1 activation.
  • Comparison of signaling pathways in SAP-deficient and Fyn-deficient T cells.

Main Results:

  • SAP-deficient T cells showed reduced IL-4 and GATA-3 induction upon TCR stimulation, independent of increased IFN-gamma.
  • While Ca(2+) and ERK signaling were intact, SAP deficiency led to impaired TCR-mediated recruitment of PKC-theta, Bcl-10 phosphorylation, IkappaB-alpha degradation, and NF-kappaB1 activation.
  • Similar signaling defects were observed in Fyn-deficient T cells.
  • SLAM engagement enhanced PKC-theta recruitment in wild-type cells but not in SAP- or Fyn-deficient cells.

Conclusions:

  • A SAP/Fyn-mediated pathway is essential for robust PKC-theta and NF-kappaB1 activation downstream of TCR and SLAM signaling.
  • This pathway plays a critical role in regulating T(H)2 cytokine production, with implications for understanding XLP pathogenesis.

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