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

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 the nature of the cDC responsible for instructing Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist, in part, due to 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 we show delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different formulations of antigen delivery, we determined that CD11b+ migratory type 2 conventional DCs (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 and antibody development, whereas loss of CD103+ cDC1s in Batf3-/- mice did not. Loss of cDC2-mediated Tfh responses was associated with impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the sub-anatomic regions of the lymph node where Tfh cell priming occurs, the T-B border. This work identifies the DC responsible for Tfh cell-dependent antibody responses, in particular when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.

ORGANISM(S): Mus musculus

PROVIDER: GSE103956 | GEO | 2017/12/01

SECONDARY ACCESSION(S): PRJNA407766

REPOSITORIES: GEO