title: Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.
abstract: DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin(+) DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Department of Dermatology/Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115 nanandasabapathy@partners.org.
authors.forename: Niroshana
authors.initials: N
authors.lastname: Anandasabapathy
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Rachel
authors.initials: R
authors.lastname: Feder
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Shamim
authors.initials: S
authors.lastname: Mollah
authors.affiliation: Department of Dermatology/Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Sze-Wah
authors.initials: SW
authors.lastname: Tse
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Longhi
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Mehandru
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Ines
authors.initials: I
authors.lastname: Matos
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Cheolho
authors.initials: C
authors.lastname: Cheong
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Darren
authors.initials: D
authors.lastname: Ruane
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Lucas
authors.initials: L
authors.lastname: Brane
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Angela
authors.initials: A
authors.lastname: Teixeira
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dobrin
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Olga
authors.initials: O
authors.lastname: Mizenina
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Chae Gyu
authors.initials: CG
authors.lastname: Park
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meredith
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, D-55131 Mainz, Germany.
authors.forename: Björn E
authors.initials: BE
authors.lastname: Clausen
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 Laboratory of Cellular Physiology and Immunology, Christopher H. Browne Center for Immunology and Immune Diseases, Hospital Informatics, and Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000145:classification / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D056724:Immunity, Humoral / Q000235:genetics; D007271:Injections, Intradermal; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008297:Male; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011506:Proteins / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000954:Antigens, Surface; C498497:Cd207 protein, mouse; D037181:Lectins, C-Type; D008024:Ligands; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D011506:Proteins; D014157:Transcription Factors; D014612:Vaccines; C574226:Zbtb46 protein, mouse; C084881:flt3 ligand protein; D007371:Interferon-gamma; D010047:Ovalbumin