Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis

Abstract

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 Tcell proliferation and their expansion of Tregs through secreted factors. ATDCs produce high levels of lactate that shape Tcell responses toward tolerance. Indeed, Tcells take up ATDC-secreted lactate, leading to a decrease of their glycolysis. Invivo, ATDCs promote elevated levels of circulating lactate and delay graft-versus-host disease by reducing Tcell proliferative capacity. The suppression of Tcell immunity through lactate production by ATDCs is a novel mechanism that distinguishes ATDCs from other cell-based immunotherapies.