Allograft Inflammatory Factor-1 Governs Hematopoietic Stem Cell Differentiation Into cDC1 and Monocyte-Derived Dendritic Cells Through IRF8 and RelB in vitro.

Diana M Elizondo,Apollo D Kacsinta,Michael W Lipscomb,Nailah Z D Brandy,Ricardo L L Da Silva,Tatiana R De Moura,Naomi L Haddock

doi:10.3389/fimmu.2019.00173

Abstract

The multistep differentiation process from hematopoietic stem cells through common myeloid progenitors into committed dendritic cell (DC) subsets remains to be fully addressed. These studies now show that Allograft Inflammatory Factor-1 (AIF1) is required for differentiation of classical DC type 1 (cDC1) subsets and monocyte-derived DC (Mo-DC). Phenotypic studies found that AIF1 expression increased in committed subsets differentiating from common myeloid progenitors (CMP). However, silencing AIF1 expression in hematopoietic stem progenitors restrained the capacity to differentiate into Mo-DC and cDC1 cell subsets under GM-CSF or Flt3-L stimuli conditions, respectively. This was further marked by restrained expression of IRF8, which is critical for development of Mo-DC and cDC1 subsets. As a result, absence of AIF1 restrained the cells at the Lin−CD117+FcγR−CD34+ CMP stage. Further biochemical studies revealed that abrogating AIF1 resulted in inhibition of the NFκB family member RelB expression and p38 MAPK phosphorylation during differentiation of Mo-DC. Lastly, protein binding studies identified that AIF1 interacts with protein kinase C (PKC) to influence downstream signaling pathways. Taken together, this is the first report showing a novel role of AIF1 as a calcium-responsive scaffold protein that supports IRF8 expression and interacts with PKC to drive NFκB-related RelB for successfully differentiating hematopoietic progenitor cells into cDC and Mo-DC subsets under Flt3-L and GM-CSF stimuli, respectively.

Highlights

Dendritic cells (DC) survey the microenvironment by capturing, processing, and presenting antigens to promote adaptive immunity [1]
The small proportion of Allograft Inflammatory Factor-1 (AIF1) expressed in the bone marrow cells were largely restricted to the lineage negative (Lin−)CD117+SCA1+CD34− subsets
AIF1 was largely found in CD11c+MHC class II+ DC, with the majority expressed in CD8α+ classical DC type 1 (cDC1) subsets

Summary

Introduction

Dendritic cells (DC) survey the microenvironment by capturing, processing, and presenting antigens to promote adaptive immunity [1]. Hematopoietic stem cells (HSC) can be directed into either common myeloid progenitors (CMP) or common lymphoid progenitors (CLP) to give rise to diverse DC subsets [2]. AIF1 Governs cDC1/Mo-DC Differentiation are all derived from the common monocyte-macrophage DC progenitor (MDP). This subset can direct generation of the common DC progenitor (CDP), which can uniquely give rise to diverse DC subsets, but not to macrophages, monocytes or other granulocyte populations [3, 4]. MDP can direct fates toward common monocyte precursors (cMoP), which can differentially give rise to monocytes that, under diverse inflammatory stimuli, generate monocyte-derived DC (MoDC), or macrophages. DC developmental processes have been extensively studied [5], the underlying mechanisms involving other fate-determining genes remain to be delineated

Methods

Results

Conclusion