title: Bcl6 and Maf cooperate to instruct human follicular helper CD4 T cell differentiation.
abstract: Follicular helper CD4 T (Tfh) cells provide B cells with signals that are important for the generation of high-affinity Abs and immunological memory and, therefore, are critical for the protective immunity elicited by most human vaccines. Transcriptional regulators of human Tfh cell differentiation are poorly understood. In this article, we demonstrate that Bcl6 controls specific gene modules for human Tfh cell differentiation. The introduction of Bcl6 expression in primary human CD4 T cells resulted in the regulation of a core set of migration genes that enable trafficking to germinal centers: CXCR4, CXCR5, CCR7, and EBI2. Bcl6 expression also induced a module of protein expression critical for T-B interactions, including SAP, CD40L, PD-1, ICOS, and CXCL13. This constitutes direct evidence for Bcl6 control of most of these functions and includes three genes known to be loci of severe human genetic immunodeficiencies (CD40L, SH2D1A, and ICOS). Introduction of Bcl6 did not alter the expression of IL-21 or IL-4, the primary cytokines of human Tfh cells. We show in this article that introduction of Maf (c-Maf) does induce the capacity to express IL-21. Surprisingly, Maf also induced CXCR5 expression. Coexpression of Bcl6 and Maf revealed that Bcl6 and Maf cooperate in the induction of CXCR4, PD-1, and ICOS. Altogether, these findings reveal that Bcl6 and Maf collaborate to orchestrate a suite of genes that define core characteristics of human Tfh cell biology.
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kroenke
authors.forename: Danelle
authors.initials: D
authors.lastname: Eto
authors.forename: Michela
authors.initials: M
authors.lastname: Locci
authors.forename: Michael
authors.initials: M
authors.lastname: Cho
authors.forename: Terence
authors.initials: T
authors.lastname: Davidson
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication; D002454:Cell Differentiation; D019743:Chemokines, CXC / Q000235:genetics / Q000276:immunology; D018920:Coculture Techniques; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics; D016086:Lentivirus; D051379:Mice; D010957:Plasmids; D021381:Protein Transport; D051560:Proto-Oncogene Proteins c-bcl-6; D051257:Proto-Oncogene Proteins c-maf / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000098546:Interleukin-21
chemical_list: C084103:BCL6 protein, human; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D007378:Interleukins; C495607:MAF protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D051257:Proto-Oncogene Proteins c-maf; D000098546:Interleukin-21