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Metabolic fitness of IgA+ plasma cells in the gut requires DOCK8

Zhang, B;Chen, S;Yin, X;McBride, CD;Gertie, JA;Yurieva, M;Bielecka, AA;Hoffmann, B;Travis Hinson, J;Grassmann, J;Xu, L;Siniscalco, ER;Soldatenko, A;Hoyt, L;Joseph, J;Norton, EB;Uthaman, G;Palm, NW;Liu, E;Eisenbarth, SC;Williams, A;

Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell intrinsic DOCK8 was required for maintenance of antigen-specific IgA secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggests that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.