2134/11310755.v1 Eros Marin Eros Marin Laurence Bouchet-Delbos Laurence Bouchet-Delbos Ophélie Renoult Ophélie Renoult Cédric Louvet Cédric Louvet Véronique Nerriere-Daguin Véronique Nerriere-Daguin Amy Managh Amy Managh Amandine Even Amandine Even Matthieu Giraud Matthieu Giraud Thien Phong Vu Manh Thien Phong Vu Manh Audrey Aguesse Audrey Aguesse Gaelle Bériou Gaelle Bériou Elise Chiffoleau Elise Chiffoleau Brigitte Alliot-Licht Brigitte Alliot-Licht Xavier Prieur Xavier Prieur Mikael Croyal Mikael Croyal James A Hutchinson James A Hutchinson Natasa Obermajer Natasa Obermajer Edward K Geissler Edward K Geissler Bernard Vanhove Bernard Vanhove Gilles Blancho Gilles Blancho Marc Dalod Marc Dalod Régis Josien Régis Josien Claire Pecqueur Claire Pecqueur Maria-Cristina Cuturi Maria-Cristina Cuturi Aurélie Moreau Aurélie Moreau Human tolerogenic dendritic cells regulate immune responses through lactate synthesis Loughborough University 2019 Lactate Immunometabolism Tolerance induction Tolerogenic dendritic cells Cell therapy in humans 2019-12-04 14:08:02 Journal contribution https://repository.lboro.ac.uk/articles/journal_contribution/Human_tolerogenic_dendritic_cells_regulate_immune_responses_through_lactate_synthesis/11310755 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.