Granulocyte Macrophage-Colony Stimulating Factor Produces a Splenic Subset of Monocyte-Derived Dendritic Cells That Efficiently Polarize T Helper Type 2 Cells in Response to Blood-Borne Antigen.

Seul Hye Ryu,Chae Gyu Park,Hyun Soo Shin,Hae-Ock Lee,Hyunju In,Soomin Hwang,Moah Sohn,Kyoung Yul Seo,Ji Soo Park,Wanho Choi,Tae-Gyun Kim,Eun-Do Kim,Min Kyung Chu,Hye Young Na,Sejung Park,Hye Hyeon Eum,Min-Geol Lee

doi:10.3389/fimmu.2021.767037

Abstract

Dendritic cells (DCs) are key antigen-presenting cells that prime naive T cells and initiate adaptive immunity. Although the genetic deficiency and transgenic overexpression of granulocyte macrophage-colony stimulating factor (GM-CSF) signaling were reported to influence the homeostasis of DCs, the in vivo development of DC subsets following injection of GM-CSF has not been analyzed in detail. Among the treatment of mice with different hematopoietic cytokines, only GM-CSF generates a distinct subset of XCR1-33D1- DCs which make up the majority of DCs in the spleen after three daily injections. These GM-CSF-induced DCs (GMiDCs) are distinguished from classical DCs (cDCs) in the spleen by their expression of CD115 and CD301b and by their superior ability to present blood-borne antigen and thus to stimulate CD4+ T cells. Unlike cDCs in the spleen, GMiDCs are exceptionally effective to polarize and expand T helper type 2 (Th2) cells and able to induce allergic sensitization in response to blood-borne antigen. Single-cell RNA sequencing analysis and adoptive cell transfer assay reveal the sequential differentiation of classical monocytes into pre-GMiDCs and GMiDCs. Interestingly, mixed bone marrow chimeric mice of Csf2rb +/+ and Csf2rb -/- demonstrate that the generation of GMiDCs necessitates the cis expression of GM-CSF receptor. Besides the spleen, GMiDCs are generated in the CCR7-independent resident DCs of the LNs and in some peripheral tissues with GM-CSF treatment. Also, small but significant numbers of GMiDCs are generated in the spleen and other tissues during chronic allergic inflammation. Collectively, our present study identifies a splenic subset of CD115hiCD301b+ GMiDCs that possess a strong capacity to promote Th2 polarization and allergic sensitization against blood-borne antigen.

Highlights

Dendritic cells (DCs) are critical antigen-presenting cells that can stimulate naive T cells [1]
We investigated the change of splenic DC subsets following injection of 3 different hematopoietic cytokines (i.e., FMS-like tyrosine kinase 3 ligand (FLT3L), MCSF, or granulocytemacrophage colony stimulating factor (GM-CSF))
We discovered a novel subset of splenic DCs (i.e., GMCSF-induced DCs (GMiDCs)) generated under GM-CSF-enriched conditions

Summary

Introduction

Dendritic cells (DCs) are critical antigen-presenting cells that can stimulate naive T cells [1]. Our previous study [2] examined the development of monocyte-derived DCs (Mo-DCs) in lymphoid organs following the in vivo challenge with a series of ligands for toll-like receptors (TLRs). We examined the role of hematopoietic cytokines related to the development of DC subsets and found that only granulocytemacrophage colony stimulating factor (GM-CSF), but neither FMS-like tyrosine kinase 3 ligand (FLT3L) nor macrophage CSF (M-CSF), were able to induce the differentiation of DCs from splenocytes in vitro [8]. Though the deletion of genes involved in GM-CSF signaling [9,10,11], the transgenic overexpression of GMCSF [10, 12,13,14], and the treatment with polyethylene glycolmodified GM-CSF [15] were shown to influence the homeostasis of DCs, the in vivo development of DC subsets following injection of GM-CSF has not been scrutinized

Methods

Results

Conclusion