Grant: Operating Grant

Germinal center (GC) is a small lymphoid structure in spleen and lymph nodes. Under normal circumstance, GC reaction can generate differentiated B lymphocytes called memory B cells and plasma cells, the latter produce antibodies that are responsible for neutralization and elimination of various viral and bacterial pathogens. However, abnormal GC reaction may lead to immune deficiency, autoimmune diseases, and even GC-derived B lymphomas that compose the majority of B cell tumors. During pathogen infection the incoming pathogens first activate B cells through B cell antigen receptors (BCR), The activated B cells then migrate to GC where they may proliferate multiple rounds, modify their antibody coding genes, and differentiate into either plasma or memory B cells. While it has become clear that coordination between B cells and other immune cells appears to be essential for GC reaction, molecular mechanisms that control B cell differentiation inside a GC remain not entirely clear. We found that Cbl proteins, a group of similar protein modifiers, play a critical role in GC reaction. We showed that Cbl proteins deficiency disrupts GC formation at multiple stages and severely impaired antibody production. We also identified that the impairment is caused by several defects, including loss of coordination between B and other immune cells and alteration of B cell function to produce high affinity antibodies (termed affinity maturation). In addition, Cbl deficient mice develop high incidence of lymphomas after immunization, indicating that they may function as tumor suppressors. The current proposal aims at understanding how Cbl proteins regulate GC reaction and antibody affinity maturation, and elucidate how Cbl deficiency contributes to B lymphoma genesis. Completion of this project will not only bring new insight in our understanding of GC reaction but also provide clues in the prevention and treatment of various immune system disorders.