Grant: Project Grant

The Germinal center (GC) is a small lymphoid structure and its function is to generate high affinity antibodies against various invading pathogens. However, abnormal regulation of the GC reaction has been linked not only to the immune deficiency but also to the production of antibodies against self, the latter may lead to the development of autoimmune diseases. GC responses involve B lymphocytes, the cells that produce antibodies after the GC reaction. While it is known that activation and differentiation of B lymphocytes into antibody secreting cells require the help from a special subset of helper T lymphocytes, called Tfh cells, the control over the development and number of Tfh cells at steady state remains not fully understood. Our preliminary studies have made significant progresses in this direction. We have found recently that Cbl proteins, a group of similar protein modifiers, play a critical role in the GC reaction. We show that genetic disruption of Cbl proteins in Tfh cells markedly increases the total number of Tfh cells. The mutation also leads to recruitment of more B cells into the GC reaction. Interestingly, the Cbl mutant mice produce more autoantibodies and die at early age, suggesting that they have developed severe autoimmune diseases. We have also conducted preliminary studies to elucidate the molecular mechanisms by which Cbls regulate Tfh biology, and found that Cbls may regulate a key cell surface receptor, called Icos, and a transcription factor, termed Bcl6, through novel protein dumping processes. These findings thus warrant further studies to understand how Cbl proteins exert their function in Tfh cell biology and antibody mediated autoimmune diseases. 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 and promote vaccination.