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Growth of B Cell Receptor Microclusters Is Regulated by PIP2 and PIP3 Equilibrium and Dock2 Recruitment and

Jing Wang1, Liling Xu1, Samina Shaheen1

  • 1MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China.

Cell Reports
|November 30, 2017
PubMed

Insights

PI3K-mediated PIP3 production fuels B cell receptor microcluster growth, essential for B cell activation. This process, regulated by PTEN and Dock2, is crucial for immune synapse formation and is altered in lupus patients.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • B cell receptor (BCR) microcluster formation upon antigen binding is a critical step for B cell activation.
  • The precise molecular mechanisms regulating BCR microcluster dynamics and their impact on B cell function remain incompletely understood.

Purpose of the Study:

  • To investigate the role of phosphoinositides, specifically phosphatidylinositol (3,4,5)-trisphosphate (PIP3), in regulating BCR microcluster growth.
  • To elucidate the involvement of PTEN and Dock2 in the PI3K-mediated signaling pathway governing BCR microcluster dynamics.
  • To examine the implications of these findings in the context of B cells from patients with systemic lupus erythematosus (SLE).

Main Methods:

  • Utilized live-cell imaging techniques to observe BCR microcluster formation and dynamics.
  • Employed biochemical assays to assess PI3K and PTEN activities and their localization.
  • Investigated the effects of Dock2 deficiency on B cell activation and immune synapse formation.
  • Analyzed primary B cells from SLE patients and healthy controls.

Main Results:

  • PI3K-dependent production of PIP3 is essential for the sustained growth of BCR microclusters.
  • PTEN negatively regulates BCR microcluster growth through its lipid phosphatase activity and plasma membrane binding.
  • PIP3 recruits and activates Dock2, which remodels the F-actin cytoskeleton, promoting microcluster growth and proper immune synapse structure.
  • B cells from SLE patients display enhanced BCR and PI3K microclusters compared to healthy controls.

Conclusions:

  • A critical balance of PIP2 and PIP3, regulated by PI3K and PTEN, governs BCR microcluster growth via Dock2.
  • This signaling pathway is fundamental for B cell activation and immune synapse formation.
  • Dysregulation of this pathway may contribute to the pathogenesis of systemic lupus erythematosus.
Keywords:
BCR microclustersDock2PI3KPIP(2)PIP(3)PTENgrowth of BCR microclusters

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