Migratory CD11b+ conventional dendritic cells induce T follicular helper cell–dependent antibody responses

Jayendra Kumar Krishnaswamy, Uthaman Gowthaman, Biyan Zhang, Johan Mattsson, Louis Szeponik, Dong Liu, Renee Wu, Theresa White, Samuele Calabro, Lan Xu, Magalie A. Collet, Marina Yurieva, Samuel Alsén, Per Fogelstrand, Anne Walter, William R. Heath, Scott N. Mueller, Ulf Yrlid, Adam Williams, Stephanie C. Eisenbarth*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding which cDC instructs Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist because of the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different antigen formulations, we determined that CD11b+ migratory type 2 cDCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2, but not CD103+ cDC1, migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell priming, whereas loss of CD103+ cDC1s in Batf3−/− mice did not. Loss of cDC2-dependent Tfh cell priming impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the subanatomic regions of the lymph node where Tfh cell priming occurs—the T-B border. This work identifies the DC subset responsible for Tfh cell–dependent antibody responses, particularly when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.

Original languageEnglish (US)
Article numbereaam9169
JournalScience Immunology
Volume2
Issue number18
DOIs
StatePublished - 2017
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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