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

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

Authors: Marin E, Bouchet-Delbos L, Renoult O, Louvet C, Nerriere-Daguin V, Managh AJ, Even A, Giraud M, Vu Manh TP, Aguesse A, Bériou G, Chiffoleau E, Alliot-Licht B, Prieur X, Croyal M, Hutchinson JA, Obermajer N, Geissler EK, Vanhove B, Blancho G, Dalod M, Josien R, Pecqueur C, Cuturi MC, Moreau A

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 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.

Link to Pubmed [PMID] – 31801055

Link to DOI – 10.1016/j.cmet.2019.11.011