The deubiquitinase activity of CYLD is required for B cell differentiation

CYLD is a functional deubiquitinase, involved in the regulation of significant cellular functions, including survival and apoptosis. To elucidate the role of CYLD in B cell differentiation, we generated transgenic animals with targeted deletion of the catalytically active form of the protein in B cells, starting from early differentiation stages. Our results indicate that catalytic inactivation of CYLD leads to a severe reduction of mature B cells, associated with blockade of differentiation at the Pro B cell stage, altered distribution of B cell populations in the spleen and bone marrow, culminating in impaired immune responses to model antigens. Single cell RNA sequencing of bone marrow B cells confirmed the severe perturbation of lymphopoiesis. Mechanistically, we found impaired expression of the IL-7 receptor alpha chain (IL-7Ra) and its upstream transcriptional activator FOXO1, leading to defective IL-7 signaling that is vital for early B cell development. However, the substrate(s) deubiquitinated by CYLD that regulates the FOXO1-IL-7R pathway remains unclear. Overall, our data imply a crucial role for the deubiquitinase activity of CYLD in B cell lymphopoiesis.