Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.

TitleClassical Flt3L-dependent dendritic cells control immunity to protein vaccine.
Publication TypeJournal Article
Year of Publication2014
AuthorsAnandasabapathy N, Feder R, Mollah S, Tse S-W, Longhi MPaula, Mehandru S, Matos I, Cheong C, Ruane D, Brane L, Teixeira A, Dobrin J, Mizenina O, Park CGyu, Meredith M, Clausen BE, Nussenzweig MC, Steinman RM
JournalJ Exp Med
Volume211
Issue9
Pagination1875-91
Date Published2014 Aug 25
ISSN1540-9538
KeywordsAnimals, Antigen Presentation, Antigens, Surface, Dendritic Cells, Female, Gene Expression, Humans, Immunity, Humoral, Injections, Intradermal, Injections, Subcutaneous, Interferon-gamma, Lectins, C-Type, Ligands, Male, Mannose-Binding Lectins, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Ovalbumin, Proteins, T-Lymphocyte Subsets, Transcription Factors, Vaccines
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.

DOI10.1084/jem.20131397
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/25135299?dopt=Abstract
Alternate JournalJ. Exp. Med.
PubMed ID25135299
PubMed Central IDPMC4144735
Grant List13013 / / PHS HHS / United States
81677 / / PHS HHS / United States
AI40045 / AI / NIAID NIH HHS / United States
AR063461-01A1 / AR / NIAMS NIH HHS / United States
FS/13/49/30421 / / British Heart Foundation / United Kingdom
K23 AR063461 / AR / NIAMS NIH HHS / United States
KL2 TR000151 / TR / NCATS NIH HHS / United States
P01 AI081677 / AI / NIAID NIH HHS / United States
R01 AI013013 / AI / NIAID NIH HHS / United States
R01 AI040045 / AI / NIAID NIH HHS / United States
RR024142 / RR / NCRR NIH HHS / United States