Migratory CD103+CD11b+ cDC2s in Peyer’s patches are critical for gut IgA responses following oral immunization

Abstract

Induction and regulation of specific intestinal IgA responses critically depend on dendritic cell subsets and the T cells they activate in the Peyer’s patches (PP). We found that oral immunization with cholera toxin (CT) as an adjuvant resulted in migration-dependent changes in the composition and localization of PP DC subsets with increased numbers of CD103- cDC2s and LysoDCs in the subepithelial dome and of CD103+ cDC2s that expressed CD101 in the T cell zones (TZ), while oral OVA tolerization was instead associated with larger quantities of TZ cDC1s and pTregs. Decreased IgA responses were observed after CT adjuvanted immunization in huCD207DTA mice lacking CD103+ cDC2s, while oral OVA tolerization was inefficient in cDC1-deficient Batf3-/- mice. Using Ovalbumin (OVA) TCR transgenic CD4 T cell adoptive transfer models, we found that co-transferred endogenous WT CD4 T cells can hinder the induction of OVA-specific IgA responses through secretion of IL-10. CT could overcome this blocking effect, apparently through a modulating effect on peripherally induced Tregs (pTreg) while promoting an expansion of follicular helper T cells (Tfh). The data support a model where cDC1-induced pTreg normally supress PP responses for any given antigen and where CT’s oral adjuvanticity effect is dependent on promoting Tfh responses through induction of CD103+ cDC2s.