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

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Science Immunology  01 Dec 2017:
Vol. 2, Issue 18, eaam9169
DOI: 10.1126/sciimmunol.aam9169

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Priming T follicular helper cells

T follicular helper (Tfh) cells play an important role in modulating antibody production by B cells. Here, Krishnaswamy et al. have examined the ability of conventional dendritic cell (cDC) subsets to prime Tfh commitment in response to intranasal immunization in mice. They report that CD11b+ migratory type 2 cDCs (cDC2s) play an essential role in promoting commitment of activated T cells to the Tfh lineage. Using microscopy to study trafficking of cDC2s after intranasal immunization, the authors demonstrate that cDC2s have the ability to carry antigens to the T-B border of the lymph node where Tfh cell priming occurs. These findings have important implications on vaccine design and delivery.


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.

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