Publication: Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis

Published in: Cell Metab 2019 Dec; 30(6): 1075-1090.e8

Authors: Eros Marín, Laurence Bouchet-Delbos, Ophélie Renoult, Cédric Louvet, Véronique Nerriere-Daguin, Amy Managh, Amandine Even, Matthieu Giraud, Thien-Phong Vu Manh, Audrey Aguesse, Gaëlle Bériou, Elise Chiffoleau, Brigitte Alliot-Licht, Xavier Prieur, Mickael Croyal, James A Hutchinson, Natasa Obermajer, Edward K. Geissler, Bernard Vanhove, Gilles Blancho, Marc Dalod, Régis Josien, Claire Pecqueur, Maria Cristina Cuturi, Aurélie Moreau

Summary

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 ATDCsecreted 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.

Link to Pubmed [PMID] – 31801055

Link to HAL – inserm-03013619

Link to DOI – 10.1016/j.cmet.2019.11.011