Metabolic Cause of Immune Cell Suppression Discovered

Not long after a threatening organism enters our bodies, our immune system springs into action and starts producing proteins known as type one interferons (IFN-I), which fight viruses and cancer, while also playing pathogenic roles in autoimmune disorders. While all cells can produce low amounts of these anti-viral and anti-tumor proteins, one particular cell type, termed plasmacytoid dendritic cells (pDCs), stands out as a specialized IFN-I producer. These specialists are capable of generating up to 1,000 times more and a broader range of IFN-I subtypes within hours of encountering a pathogen, compared with any other cell in our body. This powerful IFN-I burst is, however, short-lived. At later stages of infection and within tumors, pDCs exhibit a sharp decline in IFN-I production.

Immunologists have long focused on understanding the early, robust IFN-I response of pDCs, yet a critical gap remains: Why do pDCs stop producing IFN-I after this initial wave? What mechanisms drive their suppression at later stages of infection? Unraveling this process is key to harnessing pDC function for therapeutic interventions in infections, cancer and potentially suppressing pathogenic IFN-I in autoimmune disorders.

Professor Elina Zúñiga of the UC San Diego School of Biological Sciences and her colleagues have uncovered critical mechanisms underlying pDC suppression after infection. For the first time, the researchers identified that this suppression is linked to metabolic deficiencies, specifically the downregulation of lactate dehydrogenase B (LDHB) — an enzyme essential for metabolism and energy production. Follow-up studies demonstrated that LDHB is crucial for pDC-mediated IFN-I production, and its deficiency limits the host’s ability to control viral infections. Remarkably, restoration of LDHB in suppressed pDCs was sufficient to improve their IFN-I production capacity. The extent to which pDCs function depends on — and can be restored by — LDHB expression was a surprising discovery for the research team, highlighting metabolism as a key regulator of this potent interferon-producing cell.