title: Transcriptional programming of dendritic cells for enhanced MHC class II antigen presentation.
abstract: CD11b(+) dendritic cells (DCs) seem to be specialized for presenting antigens via major histocompatibility (MHC) class II complexes to stimulate helper T cells, but the genetic and regulatory basis for this is not established. Conditional deletion of Irf4 resulted in loss of CD11b(+) DCs, impaired formation of peptide-MHC class II complexes and defective priming of helper T cells but not of cytotoxic T lymphocyte (CTL) responses. Gene expression and chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) analyses delineated an IRF4-dependent regulatory module that programs enhanced MHC class II antigen presentation. Expression of the transcription factor IRF4 but not of IRF8 restored the ability of IRF4-deficient DCs to efficiently process and present antigen to MHC class II-restricted T cells and promote helper T cell responses. We propose that the evolutionary divergence of IRF4 and IRF8 facilitated the specialization of DC subsets for distinct modes of antigen presentation and priming of helper T cell versus CTL responses.
authors.affiliation: Department of Discovery Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Vander Lugt
authors.affiliation: Institute for Systems and Genomics Biology and Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: Aly A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, California, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hackney
authors.affiliation: Department of Discovery Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Smita
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lesch
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Meijuan
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Wyne P
authors.initials: WP
authors.lastname: Lee
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Summer
authors.initials: S
authors.lastname: Park
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Translational Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: DeVoss
authors.affiliation: Department of Discovery Immunology, Genentech, South San Francisco, California, USA.
authors.forename: Chauncey J
authors.initials: CJ
authors.lastname: Spooner
authors.affiliation: Department of Research Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Cecile
authors.initials: C
authors.lastname: Chalouni
authors.affiliation: Department of Research Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Lelia
authors.initials: L
authors.lastname: Delamarre
authors.affiliation: Department of Research Oncology, Genentech, South San Francisco, California, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.affiliation: 1] Department of Discovery Immunology, Genentech, South San Francisco, California, USA. [2].
authors.forename: Harinder
authors.initials: H
authors.lastname: Singh
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4
chemical_list: D000949:Histocompatibility Antigens Class II; D050835:Interferon Regulatory Factors; D000099185:Interferon Regulatory Factor-8; D000099218:Interferon Regulatory Factor-4