Expression of the Phosphatase Ppef2 Controls Survival and Function of CD8+ Dendritic Cells.

Markus Zwick,Charlotte Simon,Susanne Stutte,Christine Ried,Joachim L Schultze,Yi-Li Cho,Dirk H Busch,Thomas Brocker,Thomas Ulas,Leonie Grosse,Veit R Buchholz,Caroline Bernhard

doi:10.3389/fimmu.2019.00222

Abstract

Apoptotic cell death of Dendritic cells (DCs) is critical for immune homeostasis. Although intrinsic mechanisms controlling DC death have not been fully characterized up to now, experimentally enforced inhibition of DC-death causes various autoimmune diseases in model systems. We have generated mice deficient for Protein Phosphatase with EF-Hands 2 (Ppef2), which is selectively expressed in CD8+ DCs, but not in other related DC subtypes such as tissue CD103+ DCs. Ppef2 is down-regulated rapidly upon maturation of DCs by toll-like receptor stimuli, but not upon triggering of CD40. Ppef2-deficient CD8+ DCs accumulate the pro-apoptotic Bcl-2-like protein 11 (Bim) and show increased apoptosis and reduced competitve repopulation capacities. Furthermore, Ppef2−/− CD8+ DCs have strongly diminished antigen presentation capacities in vivo, as CD8+ T cells primed by Ppef2−/− CD8+ DCs undergo reduced expansion. In conclusion, our data suggests that Ppef2 is crucial to support survival of immature CD8+ DCs, while Ppef2 down-regulation during DC-maturation limits T cell responses.

Highlights

Dendritic cells (DCs) are major antigen-presenting cells (APC) located in tissues and lymphoid organs, where they integrate environmental signals to initiate either immunity or tolerance
Our data indicates that CD8+ cDC1 selectively express Phosphatase with EF-Hands 2 (Ppef2) mRNA, which is down-regulated rapidly upon DC-activation by toll-like receptor (TLR)-signaling, but not by CD40-crosslinking
In this study we show that among hematopoietic cells CD8+ cDC1 express the phosphatase Ppef2, which is down-regulated upon DC-activation by TLR-ligands, but not by CD40-engagement

Summary

Introduction

DCs are major antigen-presenting cells (APC) located in tissues and lymphoid organs, where they integrate environmental signals to initiate either immunity or tolerance. They express receptors for pathogen associated molecular patterns allowing early recognition of microbial intruders. DCs can be grouped into cDC1 and cDC2 subsets, according to their developmental origin, functional properties and location [3]. According to this nomenclature cDC1 express markers such as CD8 and CD103, while cDC2 express CD4 and CD11b. More recently it was shown that cDC1 have the specific and non-redundant role to optimize CD8+ T cell responses during a later step in T cell priming [8]

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Conclusion