Human Regulatory Dendritic Cells Develop From Monocytes in Response to Signals From Regulatory and Helper T Cells.

Xiangyue Zhang,Okmi Choi,Daniel A Winer,Michael N Alonso,Pingping Zheng,Hong Zhang,Edgar G Engleman,Yaron Carmi,Tyler R Prestwood,Nancy Wu,Eun-Suk Kang,Samuel Strober,Lorna L Tolentino

doi:10.3389/fimmu.2020.01982

Abstract

Dendritic cells (DCs) are powerful antigen presenting cells, derived from bone marrow progenitors (cDCs) and monocytes (moDCs), that can shape the immune response by priming either proinflammatory or tolerogenic immune effector cells. The cellular mechanisms responsible for the generation of DCs that will prime a proinflammatory or tolerogenic response are poorly understood. Here we describe a novel mechanism by which tolerogenic DCs are formed from monocytes. When human monocytes were cultured with CD4+FoxP3+ natural regulatory T cells (Tregs) and T helper cells (Th) from healthy donor blood, they differentiated into regulatory DCs (DCReg), capable of generating induced Tregs from naïve T cells. DCReg exhibited morphology, surface phenotype, cytokine secretion, and transcriptome that were distinct from other moDCs including those derived from monocytes cultured with Th or with GM-CSF/IL-4, as well as macrophages (MΦ). Direct cell contact between monocytes, Tregs and Th, along with Treg-derived CTLA-4, IL-10 and TGF-β, was required for the phenotypic differentiation of DCReg, although only IL-10 was required for imprinting the Treg-inducing capacity of DCReg. High ratios of Treg:Th, along with monocytes and DCReg similar in function and phenotype to those induced in vitro, were present in situ in human colorectal cancer specimens. Thus, through the combined actions of Tregs and Th, monocytes differentiate into DCs with regulatory properties, forming a positive feedback loop to reinforce Treg initiated immune regulation. This mechanism may contribute to immune tolerance in tissues such as tumors, which contain an abundance of Tregs, Th and monocytes.

Highlights

As one component of the “mononuclear phagocyte system” (MPS), monocytes constitute approximately 10% and 4% of the leukocytes in human and murine peripheral blood, respectively [1]
While monocytes that had been cultured with Tregs and T helper cells (Th) at 1:1 elicited weaker CD4+ T cell proliferative responses (Figures 1A–C) compared with those cultured with Th or Tregs alone, a significant proportion of T cells that proliferated developed into CD25highFoxP3high Tregs (Figures 1D–F)
We have demonstrated the ability of natural Tregs to promote the formation of directly induce regulatory moDCs (DCReg) directly from monocytes, and thereby reinforce an immunosuppressive environment through the induction of increased numbers of induced FoxP3+ Tregs

Summary

INTRODUCTION

As one component of the “mononuclear phagocyte system” (MPS), monocytes constitute approximately 10% and 4% of the leukocytes in human and murine peripheral blood, respectively [1]. Since Tregs most often exert direct immune suppression on Th cells [11, 13, 14], we hypothesized that both Tregs and Th might be required for the generation of immune regulatory DCs from monocytes. To evaluate this hypothesis, we cultured classical human CD14+ monocytes with activated natural Tregs and Th from healthy donors. The results show that under these conditions monocytes differentiate into regulatory DCReg with the capacity to induce the formation of immune suppressive CD4+FoxP3+ Tregs.

MATERIALS AND METHODS

RESULTS

DISCUSSION

ETHICS STATEMENT