Helminth-Conditioned Dendritic Cells Prime CD4+ T Cells to IL-4 Production In Vivo

Abstract

Dendritic cells (DC) are critical for the initiation of immune responses; however, their role in priming IL-4–producing Th2 cells in vivo is not fully understood. We used a model of intradermal injection with fluorescent-labeled, nonviable larvae from the helminth parasite nonviable Nippostrongylus brasiliensis L3 larvae (Nb), a strong inducer of Th2 responses, together with IL-4–GFP reporter mice that enable a sensitive detection of IL-4 production to examine the contribution of DC to the priming of IL-4–producing CD4+ T cells in vivo. We found that parasite material is taken up by two distinct DC populations in draining lymph nodes: a mostly CD11cintMHC class II (MHCII)hiCD11b+Ly6C− dermal DC population and a CD11chiMHCIIintCD11b+Ly6C+ monocyte-derived DC population. After Nb treatment, these two DC populations appeared in the draining lymph nodes in comparable numbers and with similar kinetics; however, treatment with pertussis toxin blocked the migration of dermal DC and the priming of IL-4–producing T cells, but only partially affected monocyte-derived DC numbers. In line with this observation, transfer of OVA-loaded CD11cintMHCIIhi DC from Nb-treated mice into naive hosts could sensitize OVA-specific CD4+ T cells to IL-4 production, whereas transfer of CD11cintMHCIIhi DC from naive mice, or CD11chiMHCIIint DC from Nb-treated or naive mice, induced CD4+ T cell expansion but no IL-4 production. Phenotypic analysis of Nb-loaded CD11cintMHCIIhi DC revealed expression of programmed death ligand 2, CD301b, IFN regulatory factor 4, and moderate upregulation of OX40 ligand. However, thymic stromal lymphopoietin and OX40 ligand were not required for Th2 priming. Thus, our data suggest that appropriate stimuli can induce DC to express the unique signals sufficient to direct CD4+ T cells to Th2 differentiation.

Suppression of colitis by adoptive transfer of helminth antigen-treated dendritic cells requires interleukin-4 receptor-α signaling

“…Infection with helminth parasites elicits IL-4 production in mammalian hosts from a variety of cells313233, with T cells activated by helminth-educated DCs being a major source of the cytokine343536. For instance, mice infected with H. diminuta have increased synthesis of IL-43738, and the demonstration that adoptive transfer of HD-DCs promotes splenocyte production of IL-4 upon reactivation in vitro is in accordance with the data from use of the parasite.…”

Klf4 Expression in Conventional Dendritic Cells Is Required for T Helper 2 Cell Responses

“…The DN migratory cDCs identified here as being Klf4 -dependent have been described recently to acquire fluorescently labeled antigen from non-viable Nippostrongylus larvae and suggested to be involved in Th2 cell responses based on in vitro analysis (Ochiai et al, 2014; Connor et al, 2014). Our results would support those conclusions by drawing a correlation between the loss of the DN cDC subset and reduced in vivo Th2 cell responses in Klf4 deficient mice.…”

Spatial regulation of IL-4 signalling in vivo

“…The activating dendritic cells do not provide decisive IL-4 [22]. Instead, it has been argued that Th2 induction results from a combination of antigen dose, select costimulatory molecules and the deliberate inhibition of conflicting signals, such as IL-12, that drive alternative T cell differentiation [19,[23][24][25][26][27]. Other innate cell types, such as basophils, may also enter the lymph node early in the immune response and provide polarising IL-4 signals [28][29][30][31].…”