Thymic but not splenic CD8⁺ DCs can efficiently cross‐prime T cells in the absence of licensing factors

Abstract

Cross-presentation is an important mechanism to elicit both immune defenses and tolerance. Although only a few DC subsets possess the machinery required for crosspresentation, little is known about differences in cross-presenting capabilities of DCs belonging to the same subpopulation but localized in different lymphoid organs. In this study, we demonstrate that steady-state thymic CD81 DCs can efficiently cross-prime naïve CD8 1 T cells in the absence of costimulation. Surprisingly, cross-priming by splenic CD8 1 DCs was dependent on licensing factors such as GM-CSF. In the absence of GM-CSF,antigen-MHC-class-I complexes were detected on thymic but not on splenic CD8 1 DCs, indicating that the cross-presentation capacity of the thymic subpopulation was higher. The observed cross-priming differences between thymic and splenic CD8 1 DCs did not correlate with differential antigen capture or costimulatory molecules found on the surface of DCs. Moreover, we did not detect overall impairment of antigen presentation, as peptide-loaded splenic CD8 1 DCs were able to induce CD8 1 T-cell proliferation. The observation that thymic CD8 1 DCs are more efficient than splenic CD8 1 DCs in T-cell cross-priming in the absence of licensing factors indicates that the requirements for efficient antigen presentation differ between these cells.

Conventional Dendritic Cells Require IRAP-Rab14 Endosomes for Efficient Cross-Presentation

“…Second, the recent finding that CD8 + DCs acquire full cross-presentation capacity only after licensing by GM-CSF, TLR ligands, or CD40 engagement (34,40) may explain why the CD8 + DC equivalents from our Flt3L-differentiated cultures did not surpass CD8…”

Development of antigen cross-presentation capacity in dendritic cells

“…In a direct comparison of the ex vivo cross-priming capabilities of CD8 + DCs isolated from thymus or spleen, the thymic CD8 + DCs are strikingly more efficient at crosspresenting soluble or cell-associated antigen than their splenic counterparts [16]. The relative impairment in cross-priming of CD8 T cells by splenic CD8 + DCs is abrogated by the addition of GM-CSF or CD40 ligands to the assay cultures; the cross-presentation efficiency of splenic or thymic CD8 + DCs is then similar [16]. Thus, although cross-presentation is an inherent property of the thymic CD8 + DCs, it is a regulated attribute of splenic CD8 + DCs (Figure 1).…”

“…It is now clear from a series of recent studies that early DCs of the CD8 + DC lineage are not born with the ability to cross-present antigens; this capability must be induced as a later developmental step [13][14][15][16]. Here, we review the studies leading to this conclusion and discuss the implications for the immune response to infections and for central tolerance in the thymus.…”

“…The processing of antigens from dead or damaged cells may be modelled using as an antigen source necrotic cells from a cell line expressing a defined antigen [13], or irradiated MHC-class-I-defective spleen cells coated with an antigen such as ovalbumin (OVA) [14,15]. Alternatively, cross-presentation of soluble protein antigens may be assayed [14][15][16], allowing separation of the antigen uptake phase from the processing and presentation phase by washing the DCs after incubation with antigen alone, then adding the readout T cells. These assays allow a measurement of the cross-presentation efficiency of the DC population, but not the activity of individual DCs.…”

“…Early CD8 + lineage DCs are deficient in crosspresentation capacity When CD8 + CD103 -DCs were isolated from the spleens of clean laboratory mice then assayed for presentation of particulate or soluble endotoxin-free antigens in media lacking TLR ligands or cytokines, they were poor at cross-presentation on MHC I, but fully capable of presentation on MHC II [13][14][15][16]. Additional factors were required to obtain good cross-presentation, indicating that it is a regulated attribute of the CD8 + DC lineage.…”