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Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis

: Marin, E.; Bouchet-Delbos, L.; Renoult, O.; Louvet, C.; Nerriere-Daguin, V.; Managh, A.J.; Even, A.; Giraud, M.; Vu Manh, T.P.; Aguesse, A.; Bériou, G.; Chiffoleau, E.; Alliot-Licht, B.; Prieur, X.; Croyal, M.; Hutchinson, J.A.; Obermajer, N.; Geissler, E.K.; Vanhove, B.; Blancho, G.; Dalod, M.; Josien, R.; Pecqueur, C.; Cuturi, M.C.; Moreau, A.


Cell metabolism 30 (2019), No.6, pp.1075-1090
ISSN: 1550-4131
ISSN: 1932-7420
Journal Article
Fraunhofer ITEM ()

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. Human autologous tolerogenic dendritic cells (ATDCs) are currently being evaluated in a clinical trial as a cell-based immunotherapy for kidney transplant recipients. Marin et al. report that ATDCs are glycolytic and produce high amounts of lactate. This secreted lactate is taken up by T cells, reducing their glycolytic flux and shifting T cell responses toward tolerance, thereby delaying graft-versus-host disease.