Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation.
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.
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada.
Mathieu
M
Gigoux
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada.
Amanda
A
Lovato
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada.
Julien
J
Leconte
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada.
Joanne
J
Leung
Department of Biochemistry, McGill University, Montréal, QC H3A 2B4, Canada.
Nahum
N
Sonenberg
Institut de recherches cliniques de Montréal (IRCM), Montréal, QC H2W 1R7, Canada; Department of Microbiology and Immunology, McGill University, Montréal, QC H3A 2B4, Canada; Department of Microbiology and Immunology, Université de Montréal, Montréal, QC H3T 1J4, Canada; Department of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada. Electronic address: woong-kyung.suh@ircm.qc.ca.
Woong-Kyung
WK
Suh
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D018920:Coculture Techniques; D039642:Eukaryotic Initiation Factors; D005434:Flow Cytometry; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015151:Immunoblotting; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D010750:Phosphoproteins / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039642:Eukaryotic Initiation Factors; D060889:Inducible T-Cell Co-Stimulator Protein; D015847:Interleukin-4; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D011948:Receptors, Antigen, T-Cell; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C499527:Eif4ebp1 protein, mouse; C556694:Icos protein, mouse; C546843:mTOR protein, mouse
Inducible costimulator; Interleukin-4; Translation