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New insights on how to harness cross-presentation for therapeutic purposes

Tang_et_al

Cross-presentation, i.e. presentation of exogenous antigens on MHC class I molecules, is essential for the induction of cytotoxic T cell responses. Manipulation of cross-presentation is an attractive therapeutic strategy, but a better understanding of the mechanisms involved is essential, especially in human.

In mouse, dendritic cells (DC) that arise from monocytes (mo-DC) during inflammation play a key role in these responses by cross-presenting antigens directly in peripheral tissues, whereas other DC cross-present in lymphoid organs. Whether human naturally-occurring mo-DC can cross-present is unknown. Here we use human mo-DC directly purified from tumor ascites to address this question. Elodie Segura and Antigen Presentation in Dendritic Cells team headed by Sebastian Amigorena found that both ascites mo-DC and macrophages cross-present efficiently, but are unable to transfer exogenous proteins into their cytosol. In addition, cross-presentation was blocked by an inhibitor of lysosomal proteases, but not of proteasome. We conclude that human monocyte-derived cells cross-present exclusively using a non-conventional proteasome-independent pathway. Finally, we found that only ascites mo-DC, but not macrophages, provide the signals necessary to efficiently induce effector cytotoxic T cells.

These results will be important for optimising therapeutic strategies aiming at modulating cross-presentation.

Human in vivo-generated monocyte-derived dendritic cells and macrophages cross-present antigens through a vacuolar pathway

Tsing-Lee Tang-Huau, Paul Gueguen, Christel Goudot, Mélanie Durand, Mylène Bohec, Sylvain Baulande, Benoit Pasquier, Sebastian Amigorena, Elodie Segura

Nature Communications, volume 9, Article number: 2570 (2018)

 

Credits: Chantraine/Institut Curie