IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Abstract

IntroductionOver the past years, it has become apparent that type-I interferons (IFNs) affect adaptive immunity through their effects on monocytes. In particular, IFN-␣ has been shown to act as a potent inducer of the rapid differentiation of human monocytes into highly activated and partially mature dendritic cells (DCs), known as IFN-DCs. 1 We demonstrated previously that human monocytes exposed to granulocyte macrophage colony-stimulating factor (GM-CSF) and IFN-␣ are rapidly induced to express a set of membrane molecules involved in antigen (Ag) presentation and T-cell costimulation, as well as to strongly promote T helper (Th)-1 response and CD8 ϩ T cell cross-priming. 2 Moreover, IFN-DCs were shown to cross-present very efficiently low amounts of nonstructural-3 protein (NS3) of hepatitis C virus (HCV) to a specific CD8 ϩ T cell clone, even in the absence of CD4 ϩ T-cell help. 2 The cross-presentation efficiency of DCs is not dictated solely by their Ag capture capability 3 ; it also is affected by critical factors such as (1) the route of Ag uptake, (2) acidification-sensitive Ag degradation in endosomal-lysosomal compartments, and (3) Ag entry into the major histocompatibility complex class-I (MHC-I) pathway. [4][5][6][7][8] At present, 4 nonmutually exclusive models have been proposed to explain cross-presentation. [8][9][10] In the canonical cytosolic pathway, endocytosed Ags are translocated into the cytosol, where they are degraded by the proteasome, and then the antigenic peptides are transported into the lumen of the endoplasmic reticulum (ER) by the transporters associated with Ag processing (TAPs), 9,10 or alternatively, reimported from the cytoplasm into the early endosomes and loaded onto endosomal 12 According to a less well-defined TAP-and proteasomeindependent endosomal pathway, Ags can be processed by endosomal proteases and loaded onto MHC-I molecules directly within early and late endosomes and lysosomes. [13][14][15] An additional model involves the delivery of components of the ER to endocytic organelles or the transport of incoming Ags to the ER. [16][17][18] Here, we have investigated the mechanisms underlying the superior efficiency of IFN-DCs in the cross-presentation of soluble proteins, by studying (1) the Ag uptake and trafficking to the class-I processing pathway, (2) the maturation kinetic of the organelles containing the internalized proteins, (3) the Ag stability within endosomes, and (4) the Ag processing and cross-presentation to specific CD8 ϩ T cells. The results reveal that IFN-DCs exhibit a delayed endosomal acidification associated with a prolonged Ag survival and retention in the early endosomal compartment, as well as with Ag trafficking to recycling pathways. In IFN-DCs, both early and recycling endosomal compartments serve as important stores of MHC-I molecules, allowing rapid presentation of exogenous Ags. These findings provide novel mechanistic insight into the cross-presentation efficiency of IFN-DCs and underscore the potential advantage of using these cellula...

Differential use of autophagy by primary dendritic cells specialized in cross-presentation

“…Prolonged antigen storage favors MHC I cross-presentation as it facilitates antigen transfer to the cytosol, rather than its rapid degradation in the lysosomes. 44,45 Indeed, LAP, the process by which LC3 is recruited to phagosomes, has recently been implicated in promoting antigen stability in DC 46 unlike in other cell types where it is proposed to enhance antigen degradation. 21,22,47 This autophagy-dependent mechanism could be of more importance for soluble antigen that is likely to be more rapidly degraded than cell-associated antigen.…”

Cationic liposomes promote antigen cross-presentation in dendritic cells by alkalizing the lysosomal pH and limiting the degradation of antigens

“…35 Compared with PBS treatment, BMDCs treated with DOTAP-CLs and DC-Chol-CLs significantly decreased DQ-OVA fluorescence, indicating the inhibition of DQ-OVA degradation (P,0.001, Figure 8). In contrast, BMDCs treated with ALs had similar levels of fluorescence as PBS-treated BMDCs, indicating antigen processing and degradation.…”

“…The DQ-OVA assay was performed as described previously 35 to study antigen processing and presentation induced by liposomes. Briefly, BMDCs (1×10 6 ) were treated overnight with different doses of liposomes.…”

NK Cell Activation in the Antitumor Response Induced by IFN-α Dendritic Cells Loaded with Apoptotic Cells from Follicular Lymphoma Patients

“…We described a new class of highly active monocyte-derived dendritic cells generated in the presence of IFN-a and GM-CSF (IFN-DC) within three days, in the absence of maturation factors and without the need for extensive operations or manipulations (7). Although IFN-DC exhibit some features of mature DC, including the ability to promote the efficient cross-priming of CD8 + cells (7)(8)(9)(10)(11), they also retain the capacity to efficiently engulf proteins and apoptotic cells. In contrast to conventional DC (IL-4-DC), IFN-DC are fully able to preserve internalized proteins from early degradation and to route Ag to the MHC class I-processing pathway, allowing long-lasting Ag presentation (9,11).…”