Key Points

The gut Th17 response is type 2 DC driven.

IL-6 is required for Th17 differentiation but does not act directly on T cells.

IL-6 is derived from type 2 DCs enriched with CD40 and CCL17/CCL21.

Abstract

Dendritic cells (DCs) are professional APCs equipped with MHC-restricted Ags, costimulations, and cytokines that effectively prime and differentiate naive T cells into distinct functional subsets. The immune signals that DCs carry reflect the route of Ag uptake and the innate stimuli they received. In the mucosal tissues, owing to the great variety of foreign Ags and inflammatory cues, DCs are predominantly activated and migratory. In the small intestine, CD4 Th17 cells are abundant and have been shown to be regulated by DCs and macrophages. Using a mouse commensal bacteria experimental model, we identified that the early priming step of commensal-driven Th17 cells is controlled by bona fide Zbtb46-expressing DCs. CCR7-dependent migration of type 2 DCs (DC2s) from the small intestine to the mesenteric lymph nodes (MLNs) is essential for the activation of naive CD4 T cells. The migratory DC2 population in the MLNs is almost exclusively Esam+ cells. Single-cell RNA sequencing highlighted the abundance of costimulatory markers (CD40 and OX40) and chemokines (Ccl22 and Cxcl16) on MLN migratory DCs. Further resolution of MLN migratory DC2s revealed that the Th17-polarizing cytokine IL-6 colocalizes with DC2s expressing CD40, Ccl17, and Ccl22. Thus, early Th17 cell differentiation is initiated by a small subset of migratory DC2s in the gut-draining lymph nodes.

Footnotes

This work was supported by National Institute of Allergy and Infectious Diseases Grant U01Al125859.

The online version of this article contains supplemental material.

S.N. designed and performed the experiments, analyzed the results, and wrote the manuscript. S.I., J.G., Y.L., C.W., and M.H. performed the experiments and analyzed the results. D.C. and C.A. performed bioinformatics analyses and provided statistical assistance. Y.Y. and B.L. conceived the project, designed the experiments, and wrote the manuscript.

Abbreviations used in this article:

DCdendritic cellDC1type 1 DCDC2type 2 DCDTdiphtheria toxinMHC IIMHC class IIMLNmesenteric lymph nodeRORretinoic acid–related orphan receptorSFBsegmented filamentous bacteriascRNA-seqsingle-cell RNA sequencingSILPsmall intestinal lamina propriaTregT regulatoryReceived March 18, 2022.Accepted July 12, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.