L-asparaginase reversibly suppresses CD40-mediated B cell activation and antigen-presenting function by metabolic restriction.

Metabolic reprogramming and nutrient uptake are essential for immune cell activation and adaptation. While asparagine is normally a non-essential amino acid, extracellular depletion by L-asparaginase (ASNase) is widely used to treat acute lymphoblastic leukemia and lymphoma. However, its effects on non-malignant B cells remain poorly understood. Using a model of CD40-mediated human B cell activation, we investigated the impact of ASNase on primary human B cells. Even at low, clinically sub-therapeutic concentrations, ASNase induced profound metabolic alterations, reducing glycolytic and mitochondrial respiratory capacity. This was accompanied by impaired proliferation and cluster formation without increasing cell death. Instead, ASNase suppressed B cell activation and antigen-presenting cell (APC) function while promoting the emergence of regulatory B cell phenotypes and immunosuppressive cytokine expression in a subset of cells. Supplementation with asparagine or glutamine restored APC function and proliferation, with glutamine showing slightly greater efficacy. These findings suggest that ASNase reversibly suppresses pro-inflammatory B cell functions through extensive metabolic reprogramming and may warrant evaluation as a potential immunosuppressive agent.