Kinesin-1 regulates antigen cross-presentation through the scission of tubulations from early endosomes in dendritic cells

Meriem Belabed,Nicolas Goudin,Jian-Dong Huang,François-Xavier Mauvais,Fernando E Sepulveda,Alain Fischer,Sophia Maschalidi,Peter Van Endert,Geneviève De Saint Basile,Mathieu Kurowska,Gaël Ménasché

doi:10.1038/s41467-020-15692-0

Abstract

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. Although cross-presentation depends critically on the trafficking of Ag-containing intracellular vesicular compartments, the molecular machinery that regulates vesicular transport is incompletely understood. Here, we demonstrate that mice lacking Kif5b (the heavy chain of kinesin-1) in their DCs exhibit a major impairment in cross-presentation and thus a poor in vivo anti-tumour response. We find that kinesin-1 critically regulates antigen cross-presentation in DCs, by controlling Ag degradation, the endosomal pH, and MHC-I recycling. Mechanistically, kinesin-1 appears to regulate early endosome maturation by allowing the scission of endosomal tubulations. Our results highlight kinesin-1’s role as a molecular checkpoint that modulates the balance between antigen degradation and cross-presentation.

Highlights

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours
The Ag processing for the crosspresentation can occur in a proteasome- and TAPindependent pathway known as the vacuolar pathway, in which Ag degradation requires the activity of acidic endosomal proteases and is followed by peptide loading onto MHC-I molecules within endosomes[12]
Given that trafficking of intracellular vesicular compartments is necessary for Ag cross-presentation, we assessed the role of the conventional microtubule-dependent motor protein kinesin-1 in Ag presentation by DCs

Summary

Introduction

Dendritic cells (DCs) constitute a specialized population of immune cells that present exogenous antigen (Ag) on major histocompatibility complex (MHC) class I molecules to initiate CD8 + T cell responses against pathogens and tumours. During cross-presentation, extracellular Ags are internalised within specialised organelles termed phagosomes (for particulate Ags such as microbes or dead cells) or endosomes (for soluble Ags) Both compartments subsequently mature through fusion with late endosomes or lysosomes. This fusion leads to a slight acidification of organelles via the recruitment of V-ATPase and the NADPH oxidase 2 complex (NOX2), and the delivery of degrading enzymes that partially mediate Ag proteolysis[5,6]. Apart from the kinesin-1based transport of late endosomes/lysosomes towards their secretion site upon cell activation, few studies have looked at the role of this molecular motor in the regulation of early endosome and recycling endosome trafficking[20,21,22]. Our results show that kinesin-1 (i) has an essential role in the Ag and MHC-I endocytic trafficking upstream of cross-presentation, and (ii) regulates early endosome movement and maturation via the fission of endosomal tubulations

Methods

Results

Conclusion