The Innate Immune Response to Infection Induces Erythropoietin-Dependent Replenishment of the Dendritic Cell Compartment.

Henrik Einwächter,Heiko Adler,Wolfgang Reindl,Ulrich H Koszinowski,Lars Dölken,Alexander Heiseke,Zsolt Ruzsics,David Voehringer,Georg Gasteiger,Andreas Schlitzer,Stefan Jordan,Markus G Manz,Tim Sparwasser

doi:10.3389/fimmu.2020.01627

Abstract

Dendritic cells (DC) play a key role in the adaptive immune response due to their ability to present antigens and stimulate naïve T cells. Many bacteria and viruses can efficiently target DC, resulting in impairment of their immunostimulatory function or elimination. Hence, the DC compartment requires replenishment following infection to ensure continued operational readiness of the adaptive immune system. Here, we investigated the molecular and cellular mechanisms of inflammation-induced DC generation. We found that infection with viral and bacterial pathogens as well as Toll-like receptor 9 (TLR9) ligation with CpG-oligodeoxynucleotide (CpG-ODN) expanded an erythropoietin (EPO)-dependent TER119+CD11a+ cell population in the spleen that had the capacity to differentiate into TER119+CD11chigh and TER119−CD11chigh cells both in vitro and in vivo. TER119+CD11chigh cells contributed to the conventional DC pool in the spleen and specifically increased in lymph nodes draining the site of local inflammation. Our results reveal a so far undescribed inflammatory EPO-dependent pathway of DC differentiation and establish a mechanistic link between innate immune recognition of potential immunosuppressive pathogens and the maintenance of the DC pool during and after infection.

Highlights

Dendritic cells (DC) are professional antigen-presenting cells crucial for coordinating and regulating immune responses
The obtained cells presented the distinct morphology of DC (Figure 1B) and could be separated into immature and mature populations according to the expression of major histocompatibility complex (MHC) class II molecules like DC generated from bone marrow culture (BMDC) (Figure 1C and Figures S1A,B)
We tested whether increased number of CD11c+ and TER119+ cells were linked and found a distinct TER119+CD11chigh population that appeared in CpG-ODN–stimulated spleens but not in the bone marrow (Figure 1G and Figures S1D,F)

Summary

Introduction

Dendritic cells (DC) are professional antigen-presenting cells crucial for coordinating and regulating immune responses. The origin and the development of DC has been intensively studied [1] Based on their ontogeny, the DC family can be subdivided into four cell types: Langerhans cells, plasmacytoid DC (pDC), conventional DC (cDC) and monocyte-derived DC [2]. Langerhans cells are seeded in the skin during embryonic development or derive from monocytes during inflammation [3, 4]. CDC and pDC both originate from a pluripotent hematopoietic stem cell in the bone marrow [5]. PDC fully develop in the bone marrow and only mature in the periphery [6]. CDC fully differentiate into cDC subpopulations cDC1 and cDC2 depending on the transcription factors BATF3 and IRF4 [9], respectively, and acquire subset-specific functions. It is important to note that even during later stages of lineage commitment DC development retains a certain plasticity, as for example pDC precursors can re-differentiate into cDC in the periphery [10]

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Results

Conclusion