Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation

Mol Immunol. 2014 May;59(1):46-54. doi: 10.1016/j.molimm.2014.01.008. Epub 2014 Jan 31.

Abstract

The inducible costimulator (ICOS) is highly expressed in follicular helper T (Tfh) cells, a subset of CD4 T cells that migrate into the B cell zone and facilitate germinal center reactions. Although ICOS is known to play a critical role in forming the Tfh cell population during immune responses, its contribution to the effector functions of Tfh cells remains unclear. Using activated mouse splenic CD4 T cells we demonstrate that ICOS assists TCR-mediated signal transduction by potentiating the PI3K-AKT-mTOR signaling cascade that leads to hyper-phosphorylation of p70S6K and 4E-BP1, events that are known to augment cap-dependent mRNA translation. Consequently, ICOS costimulation promotes the formation of polysomes on IL-4 mRNA in a PI3K-dependent manner. Furthermore, we show that the supply of IL-4 becomes a limiting factor for T-dependent B cell activation during in vitro co-culture when the ICOS-PI3K signaling axis is disrupted in T cells. This ICOS costimulation-dependent translational control may ensure targeted delivery of IL-4 to cognate B cells during T-B collaborations in the germinal center.

Keywords: Inducible costimulator; Interleukin-4; Translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cells, Cultured
  • Coculture Techniques
  • Eukaryotic Initiation Factors
  • Flow Cytometry
  • Germinal Center / cytology
  • Germinal Center / immunology
  • Germinal Center / metabolism
  • Immunoblotting
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Inducible T-Cell Co-Stimulator Protein / immunology*
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology*
  • Interleukin-4 / metabolism
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Phosphatidylinositol 3-Kinases / immunology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / immunology
  • Phosphoproteins / metabolism
  • Phosphorylation / immunology
  • Proto-Oncogene Proteins c-akt / immunology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Protein S6 Kinases, 70-kDa / immunology
  • Ribosomal Protein S6 Kinases, 70-kDa / metabolism
  • Signal Transduction / immunology
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / immunology*
  • T-Lymphocytes, Helper-Inducer / metabolism
  • TOR Serine-Threonine Kinases / immunology
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eukaryotic Initiation Factors
  • Icos protein, mouse
  • Inducible T-Cell Co-Stimulator Protein
  • Phosphoproteins
  • Receptors, Antigen, T-Cell
  • Interleukin-4
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases, 70-kDa
  • TOR Serine-Threonine Kinases