title: A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1.
abstract: Signaling via the inducible costimulator ICOS fuels the stepwise development of follicular helper T cells (TFH cells). However, a signaling pathway unique to ICOS has not been identified. We found here that the kinase TBK1 associated with ICOS via a conserved motif, IProx, that shares homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2 and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) TFH cells and the development of GCs, interfered with B cell differentiation and disrupted the development of antibody responses, but the IProx motif and TBK1 were dispensable for the early differentiation of TFH cells. These results reveal a previously unknown ICOS-TBK1 signaling pathway that specifies the commitment of GC TFH cells.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pedros
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Yaoyang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Joyce K
authors.initials: JK
authors.lastname: Hu
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Canonigo-Balancio
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: John R
authors.identifier: 0000-0001-5267-1672
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Division of Infectious Diseases, School of Medicine, University of California San Diego, La Jolla, California, USA.
authors.forename: Shane
authors.identifier: 0000-0002-6484-6262
authors.initials: S
authors.lastname: Crotty
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Kok-Fai
authors.initials: KF
authors.lastname: Kong
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D001402:B-Lymphocytes / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D047992:TNF Receptor-Associated Factor 2; D048008:TNF Receptor-Associated Factor 3; C498588:Tbk1 protein, mouse; D017346:Protein Serine-Threonine Kinases