title: A p85α-osteopontin axis couples the receptor ICOS to sustained Bcl-6 expression by follicular helper and regulatory T cells.
abstract: Follicular helper T cells (TFH cells) and follicular regulatory T cells (TFR 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 TFH cells and TFR 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 TFH cells and TFR cells; this suggests new therapeutic avenues to manipulate the responses of these cells.
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology &Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jianmei W
authors.initials: JW
authors.lastname: Leavenworth
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology &Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bert
authors.initials: B
authors.lastname: Verbinnen
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Cell Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yin
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Parasitology, Wenzhou Medical College, Wenzhou, China.
authors.forename: Huicong
authors.initials: H
authors.lastname: Huang
authors.affiliation: 1] Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Microbiology &Immunobiology, Division of Immunology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics / Q000276:immunology*; D020033:Protein Isoforms; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics / Q000276:immunology*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D020033:Protein Isoforms; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; C506896:Spp1 protein, mouse; D053495:Osteopontin; D058543:Class Ia Phosphatidylinositol 3-Kinase