Human tolerogenic dendritic cells regulate immune responses through lactate synthesis
journal contribution
posted on 2019-12-04, 14:08authored byEros Marin, Laurence Bouchet-Delbos, Ophélie Renoult, Cédric Louvet, Véronique Nerriere-Daguin, Amy ManaghAmy Managh, Amandine Even, Matthieu Giraud, Thien Phong Vu Manh, Audrey Aguesse, Gaelle Bériou, Elise Chiffoleau, Brigitte Alliot-Licht, Xavier Prieur, Mikael Croyal, James A Hutchinson, Natasa Obermajer, Edward K Geissler, Bernard Vanhove, Gilles Blancho, Marc Dalod, Régis Josien, Claire Pecqueur, Maria-Cristina Cuturi, Aurélie Moreau
Cell therapy is a promising strategy for treating patients suffering from autoimmune or inflammatory diseases or receiving a transplant. Based on our preclinical studies, we have generated human autologous tolerogenic dendritic cells (ATDCs), which are being tested in a first-in-man clinical trial in kidney transplant recipients. Here, we report that ATDCs represent a unique subset of monocyte-derived cells based on phenotypic, transcriptomic, and metabolic analyses. ATDCs are characterized by their suppression of T cell proliferation and their expansion of Tregs through secreted factors. ATDCs produce high levels of lactate that shape T cell responses toward tolerance. Indeed, T cells take up ATDC-secreted lactate, leading to a decrease of their glycolysis. In vivo, ATDCs promote elevated levels of circulating lactate and delay graft-versus-host disease by reducing T cell proliferative capacity. The suppression of T cell immunity through lactate production by ATDCs is a novel mechanism that distinguishes ATDCs from other cell-based immunotherapies.
This paper was accepted for publication in the journal Cell Metabolism and the definitive published version is available at https://doi.org/10.1016/j.cmet.2019.11.011.