Human Tolerogenic Dendritic Cells Regulate Immune Responses through Lactate Synthesis

Area of Science:

• Immunology
• Cell Therapy
• Transplantation Immunology

Background:

• Cell therapy offers a promising approach for managing autoimmune diseases, inflammatory conditions, and transplant rejection.
• Human autologous tolerogenic dendritic cells (ATDCs) have been developed and are undergoing clinical evaluation in kidney transplant recipients.

Purpose of the Study:

• To characterize human autologous tolerogenic dendritic cells (ATDCs) as a unique cell subset.
• To elucidate the mechanisms by which ATDCs modulate T-cell responses and promote immune tolerance.
• To investigate the role of ATDCs in a clinical setting, specifically in kidney transplant recipients.

Main Methods:

• Phenotypic, transcriptomic, and metabolic analyses were employed to define ATDCs.
• Assays were conducted to assess the impact of ATDCs on T-cell proliferation and regulatory T-cell (Treg) expansion.
• Measurement of lactate production by ATDCs and its uptake by T-cells.
• In vivo studies to evaluate the effects of ATDCs on graft-versus-host disease and circulating lactate levels.

Main Results:

• ATDCs were identified as a distinct monocyte-derived cell subset with potent T-cell suppressive capabilities.
• ATDCs expand regulatory T-cells (Tregs) via secreted factors and produce high levels of lactate.
• T-cells exposed to ATDC-secreted lactate exhibit decreased glycolysis, promoting a tolerogenic phenotype.
• In vivo administration of ATDCs led to increased circulating lactate and delayed graft-versus-host disease by reducing T-cell proliferation.

Conclusions:

• ATDCs represent a unique cell-based immunotherapy characterized by lactate production.
• The mechanism of T-cell suppression through lactate secretion distinguishes ATDCs from other immunotherapies.
• ATDCs hold significant potential for improving outcomes in transplantation and treating immune-mediated diseases.