A p85α-osteopontin axis couples the receptor ICOS to sustained Bcl-6 expression by follicular helper and regulatory T cells

Academic Article

Abstract

  • Follicular helper T cells (T FH cells) and follicular regulatory T cells (T FR cells) regulate the quantity and quality of humoral immunity. Although both cell types express the costimulatory receptor ICOS and require the transcription factor Bcl-6 for their differentiation, the ICOS-dependent pathways that coordinate their responses are not well understood. Here we report that activation of ICOS in CD4+ T cells promoted interaction of the p85α regulatory subunit of the signaling kinase PI(3)K and intracellular osteopontin (OPN-i), followed by translocation of OPN-i to the nucleus, its interaction with Bcl-6 and protection of Bcl-6 from ubiquitin-dependent proteasome degradation. Post-translational protection of Bcl-6 by OPN-i was essential for sustained responses of T FH cells and T FR cells and regulation of the germinal center B cell response to antigen. Thus, the p85α-OPN-i axis represents a molecular bridge that couples activation of ICOS to Bcl-6-dependent functional differentiation of T FH cells and T FR cells; this suggests new therapeutic avenues to manipulate the responses of these cells.
  • Published In

  • Nature Immunology  Journal
  • Digital Object Identifier (doi)

    Author List

  • Leavenworth JW; Verbinnen B; Yin J; Huang H; Cantor H
  • Start Page

  • 96
  • End Page

  • 106
  • Volume

  • 16
  • Issue

  • 1