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 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 or knockout mice, respectively, led to reduced Tfh cell priming, whereas loss of CD103 cDC1s in 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.

T follicular helper cell heterogeneity: Time, space, and function

“…17,18 The early pre-Tfh cell phenotype is also governed by the transcription factor ASCL2, which binds the Cxcr5 locus to directly upregulate CXCR5 and downregulate expression of CCR7 and PSGL-1 in a Bcl6independent manner. 35,[37][38][39] While CD25 is proposed to quench surrounding IL-2 to promote Tfh cell differentiation, 37 ICOS-ICOSL and OX40-OX40L interactions both favor Tfh cell development through activation of PI3K and Akt signaling. In mice, Tfh cell development relies on IL-6 and IL-21 signaling through the transcription factor STAT3, with loss of either cytokine impairing cell differentiation.…”

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

“…Additionally, Dock8-lacking dendritic cells show impaired interstitial migration within the dermis and through the subcapsular sinus floor of lymph nodes in mice; this, in turn, impairs priming of T cells in the lymph nodes36,37 (Figure 1B). More recently, the migration of CD11b + migratory type 2 conventional dendritic cells was shown to be selectively impaired, leading to failure to prime for follicular T helper cell (T F H) differentiation, which in turn impaired production of high-affinity, class-switched antibodies in a mouse model of influenza virus infection 38. Thus, impaired dendritic cell functions could indirectly compromise T and B cell responses directed against virus pathogens in DIDS patients.5 | OTHER INFEC TI ON SDIDS patients typically present in infancy with eczema, which can be complicated by abscesses, cellulitis, or other soft tissue bacterial infections 17.…”

Indoor dust acts as an adjuvant to promote sensitization to peanut through the airway

“…33,35 Moreover, cDC2s were recently reported to induce Tfh cell responses against inhaled antigens, although this study was performed in the absence of Th2 adjuvants and therefore IgE responses could not be assessed. 32 However, we and others have previously found that lung cDC1s from ID-exposed mice are capable of stimulating Th2 cell differentiation. 34,42 Furthermore, both gut and splenic cDC1s have been shown to prime antigen-specific Tfh cells' cell responses, 76,77 raising the possibility that lung cDC1s may do the same under certain conditions.…”

“…This observation is intriguing, as lung cDC2s have been reported to be the primary DC subset that induces allergic responses against inhaled allergens . Moreover, cDC2s were recently reported to induce Tfh cell responses against inhaled antigens, although this study was performed in the absence of Th2 adjuvants and therefore IgE responses could not be assessed . However, we and others have previously found that lung cDC1s from ID‐exposed mice are capable of stimulating Th2 cell differentiation .…”

“…Accordingly, recent studies have shown that Tfh cells are essential for the development of IgE responses against inhaled antigens . Like other T helper cell subsets, cDCs are necessary for priming antigen‐specific Tfh cells . While several studies have investigated the role of lung cDCs in promoting Th2 responses, the mechanisms by which lung cDCs prime allergen‐specific Tfh cells remain poorly understood.…”