Cross-dressed dendritic cells drive memory CD8+ T-cell activation after viral infection

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Abstract
A novel mechanism for the activation of naive CD8+ T cells was identified in 2005. Termed cross-dressing, in recognition of the cross-priming and direct priming mechanisms known previously, it involves the transfer of loaded MHC/peptide molecules from an infected cell to dendritic cells. Linda Wakim and Michael Bevan now show that memory T-cell activation in viral infection occurs in part through cross-dressing. As an alternative mode of antigen presentation to memory T cells during viral infection, cross-dressing avoids the need for antigen processing by the presenting dendritic cell and allows prompt presentation of peptide epitopes that closely reflect those expressed on infected cells. This study shows that memory T-cell activation in viral infection occurs, in part, by cross-dressing; that is, the transfer of loaded MHC-peptide molecules from an infected cell to dendritic cells. After an infection, cytotoxic T lymphocyte precursors proliferate and become effector cells by recognizing foreign peptides in the groove of major histocompatibility complex (MHC) class I molecules expressed by antigen-presenting cells (APCs)1. Professional APCs specialized for T-cell activation acquire viral antigen either by becoming infected themselves (direct presentation) or by phagocytosis of infected cells, followed by transfer of antigen to the cytosol, processing and MHC class I loading in a process referred to as cross-presentation2. An alternative way, referred to as ‘cross-dressing’, by which an uninfected APC could present antigen was postulated to be by the transfer of preformed peptide–MHC complexes from the surface of an infected cell to the APC without the need of further processing3. Here we show that this mechanism exists and boosts the antiviral response of mouse memory CD8+ T cells. A number of publications have demonstrated sharing of peptide-loaded MHC molecules in vitro4,5,6,7. Our in vitro experiments demonstrate that cross-dressing APCs do not acquire peptide–MHC complexes in the form of exosomes released by donor cells. Rather, the APCs and donor cells have to contact each other for the transfer to occur. After a viral infection, we could isolate cross-dressed APCs able to present viral antigen in vitro. Furthermore, using the diphtheria toxin system to selectively eliminate APCs that could only acquire viral peptide–MHC complexes by cross-dressing, we show that such presentation can promote the expansion of resting memory T cells. Notably, naive T cells were excluded from taking part in the response. Cross-dressing is a mechanism of antigen presentation used by dendritic cells that may have a significant role in activating previously primed CD8+ T cells.