Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis

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.