Elizabeth A Thompson, Alexis Figueroa, Katerina Roznik, Nicole E Skinner, Santosh Dhakal, Shuai Li, Luca Biavati, Laura A Sena, Laila Stoddart, Karli Redinger, Samuel B Warner, Sabra L Klein, Nadine Rouphael, Joel N Blankson, Yolanda Eby, Robert D Leone, Peter S Heeger, Mark A Robien, Christian P Larsen, Erika L Pearce, Edward J Pearce, Hongkai Ji, Andrew H Karaba, Dorry L Segev, Aaron Ar Tobian, William A Werbel, Andrea L Cox, Justin R Bailey
Pharmacologic immunosuppression is essential for preventing organ rejection and controlling autoimmunity, but profoundly impairs humoral immunity, increasing the risk of vaccine failure and infection. The mechanisms by which immunosuppressive therapies disrupt human B cell responses remain poorly defined. Here, we identified dysregulated lipid metabolism as a central determinant of impaired vaccine response in solid organ transplant recipients (SOTRs). Using high-dimensional immune profiling, single-cell transcriptomics, and functional metabolic assays, we found that effective B cell responses required a homeostatic balance between lipid synthesis and fatty acid oxidation. The widely used immunosuppressive agent, mycophenolic acid (MPA) was strongly associated with vaccine non-response and induced excessive lipid synthesis, lipid accumulation, and mitochondrial stress in B cells. In contrast, CD11c+ B cells retained the capacity to differentiate into plasmablasts in the presence of MPA through elevated expression of CPT1A, a mitochondrial fatty acid transporter, and enhanced fatty acid oxidation. These cells were found to be a key feature of early effective vaccine responses in healthy individuals and SOTRs. Notably, pharmacologic inhibition of cholesterol synthesis partially restored plasmablast differentiation in the presence of MPA. These findings identify B cell lipid metabolism as a critical and targetable regulator of human humoral immunity during immunosuppression.