CD11b+ lung dendritic cells at different stages of maturation induce Th17 or Th2 differentiation

Gentaro Izumi,Sara A Grimm,Keiko Nakano,Donald N Cook,Hideki Nakano,Gregory S Whitehead,Peer W Karmaus,Michael B Fessler

doi:10.1038/s41467-021-25307-x

Abstract

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b+ DCs (cDC2) are heterogeneous. Here, we report a population of cDCs that rapidly accumulates in lungs of mice following house dust extract inhalation. These cells are Ly-6C+, are developmentally and phenotypically similar to cDC2, and strongly promote Th17 differentiation ex vivo. Single cell RNA-sequencing (scRNA-Seq) of lung cDC2 indicates 5 distinct clusters. Pseudotime analysis of scRNA-Seq data and adoptive transfer experiments with purified cDC2 subpopulations suggest stepwise developmental progression of immature Ly-6C+Ly-6A/E+ cDC2 to mature Ly-6C–CD301b+ lung resident cDC2 lacking Ccr7 expression, which then further mature into CD200+ migratory cDC2 expressing Ccr7. Partially mature Ly-6C+Ly-6A/E–CD301b– cDC2, which express Il1b, promote Th17 differentiation. By contrast, CD200+ mature cDC2 strongly induce Th2, but not Th17, differentiation. Thus, Th17 and Th2 differentiation are promoted by lung cDC2 at distinct stages of maturation.

Highlights

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b+ dendritic cells (DCs) are heterogeneous
These results suggest that lung-resident Conventional DCs (cDCs) can promote the development of allergen-specific Th17 cells
Total lung DCs isolated from house-dust extract (HDE)/OVA-treated mice primed the development of IL-17-producing Th17 cells, as well as IL-13-producing Th2 cells (Fig. 1c), in agreement with a previous report[33]

Summary

Introduction

Dendritic cells (DC) in the lung that induce Th17 differentiation remain incompletely understood, in part because conventional CD11b+ DCs (cDC2) are heterogeneous. It is well established that T cell differentiation is induced in the tissue-draining lymph nodes (LNs)[28], but lung cDC2 are less migratory than cDC129, suggesting that some effector T cells might be induced by lung-resident cDCs. In this work, we utilize mass cytometry, single-cell RNA sequencing (scRNA-Seq), and ex vivo studies to identify and functionally analyze discrete cDC2s in the lungs of mice following house-dust extract (HDE) inhalation. We utilize mass cytometry, single-cell RNA sequencing (scRNA-Seq), and ex vivo studies to identify and functionally analyze discrete cDC2s in the lungs of mice following house-dust extract (HDE) inhalation These cDC2s resolve into five distinct clusters that differ in their maturational status and ability to induce helper T cell differentiation. Whereas partially mature Ly-6C+CD301b– cDC2 lack Ccr[7] expression and promote

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