Differential uptake and cross‐presentation of soluble and necrotic cell antigen by human DC subsets

Abstract

Cross-presentation is the mechanism by which exogenous Ag is processed for recognition by CD8 + T cells. Murine CD8α + DCs are specialized at cross-presenting soluble and cellular Ag, but in humans this process is poorly characterized. In this study, we examined uptake and cross-presentation of soluble and cellular Ag by human blood CD141 + DCs, the human equivalent of mouse CD8α + DCs, and compared them with human monocyte-derived DCs (MoDCs) and blood CD1c + DC subsets. MoDCs were superior in their capacity to internalize and cross-present soluble protein whereas CD141 + DCs were more efficient at ingesting and cross-presenting cellular Ag. Whilst cross-presentation by CD1c + DCs and CD141 + DCs was dependent on the proteasome, and hence cytosolic translocation, cross-presentation by MoDCs was not. Inhibition of endosomal acidification enhanced cross-presentation by CD1c + DCs and MoDCs but not by CD141 + DCs. These data demonstrate that CD1c + DCs, CD141 + DCs, and MoDCs are capable of crosspresentation; however, they do so via different mechanisms. Moreover, they demonstrate that human CD141 + DCs, like their murine CD8α + DC counterparts, are specialized at cross-presenting cellular Ag, most likely mediated by an enhanced capacity to ingest cellular Ag combined with subtle changes in lysosomal pH during Ag processing and use of the cytosolic pathway.Keywords: Antigen processing r Cross-presentation r Human dendritic cells Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDendritic cells (DCs) are professional APCs that are uniquely able to process and present antigen (Ag) to prime naïve T-cell Correspondence: Dr. Kristen J. Radford e-mail: kristen.radford@mater.uq.edu.au responses. DCs in human and mouse can be classified into a number of subsets that vary in location, phenotype, and specialized function [1]. These include (i) inflammatory monocyte-derived DCs (MoDCs) that develop from monocytes and are rapidly * These authors contributed equally to this work.C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 330 Meng-Chieh Chiang et al. Eur. J. Immunol. 2016. 46: 329-339 recruited to sites of inflammation, (ii) plasmacytoid DCs, which are key producers of type I IFN, and (iii) "classical" or "conventional" DCs (cDCs), which can be further categorized based on location into "lymphoid-resident" and "migratory" DCs [1]. The lymphoidresident DCs capture Ag directly in situ, whereas migratory DCs reside in the peripheral organs (e.g. lung, skin, and gut) where they capture Ag then migrate to lymphoid tissues to share their Ag with other lymphoid-resident DCs, or present Ag directly to T cells. cDCs can be further segregated into two main subsets: (i) the mouse CD11b + cDC subset and human CD1c + DC equivalent; and (ii) the mouse CD8α + lymphoid-resident DC, related mouse CD103 + tissue resident cDCs, and the human equivalent CD141 + DC that can now be collectively defined by coexpression of the C-type lectin-like re...

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“…There are many subsets of DCs that can be distinguished based on their origin and/or expression of various cell surface markers and many of these can cross-present antigen in vitro (13, 152–155). When the DCs that are actually cross-presenting antigens in mice have been characterized, they are most often the ones that express the chemokine receptor XCR1 (156) plus CD8 (15, 16, 157) and/or CD103 (158, 159).…”

“…In humans the equivalent XCR1+ cross-presenting DC is thought to be BDCA3+ XCR1+ CD141+ and these cells are also efficient at XPT by the P2C in vitro. (152, 165, 166). …”

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