Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway

J Exp Med. 2017 Apr 3;214(4):931-941. doi: 10.1084/jem.20160972. Epub 2017 Mar 24.

Abstract

Transient suppression of B cell function often accompanies acute viral infection. However, the molecular signaling circuitry that enforces this hyporesponsiveness is undefined. In this study, experiments identify up-regulation of the inositol phosphatase PTEN (phosphatase and tensin homolog) as primarily responsible for defects in B lymphocyte migration and antibody responses that accompany acute viral infection. B cells from mice acutely infected with gammaherpesvirus 68 are defective in BCR- and CXCR4-mediated activation of the PI3K pathway, and this, we show, is associated with increased PTEN expression. This viral infection-induced PTEN overexpression appears responsible for the suppression of antibody responses observed in infected mice because PTEN deficiency or expression of a constitutively active PI3K rescued function of B cells in infected mice. Conversely, induced overexpression of PTEN in B cells in uninfected mice led to suppression of antibody responses. Finally, we demonstrate that PTEN up-regulation is a common mechanism by which infection induces suppression of antibody responses. Collectively, these findings identify a novel role for PTEN during infection and identify regulation of the PI3K pathway, a mechanism previously shown to silence autoreactive B cells, as a key physiological target to control antibody responses.

MeSH terms

  • Animals
  • Antibody Formation
  • B-Lymphocytes / immunology*
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • PTEN Phosphohydrolase / physiology*
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / physiology
  • Phosphoinositide-3 Kinase Inhibitors*
  • Receptors, Antigen, B-Cell / physiology
  • Receptors, CXCR4 / physiology
  • Signal Transduction / physiology*
  • Virus Diseases / immunology*

Substances

  • CXCR4 protein, mouse
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Antigen, B-Cell
  • Receptors, CXCR4
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Inpp5d protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases