September 12, 2023
Wei Cheng with Students

[Ann Arbor, August 31st 2023] — In a viral infection, the B lymphocytes in the body immune system can recognize viruses and produce antibodies to fight off viruses, which is an essential body defense mechanism against many natural viral infections.  This process is also the basis for the development of many modern antiviral vaccines, however, the precise mechanisms behind B cell recognition of viruses have long remained elusive.

A groundbreaking new study published in Nature Immunology on August 31st, 2023 ( sheds light on the remarkable potency of B cells to viral infections. In a joint effort led by Dr. Wei Cheng at the University of Michigan College of Pharmacy and Dr. Julie Zikherman at the University of California San Francisco, they have unveiled the molecular basis for the rapid and robust B cell responses to viruses.  This work provides crucial insights into the body's defense mechanisms against viral invaders.

“I have been long thinking about this question and the right approach to answer this question.” Cheng said.  B lymphocytes, serving as immune surveillance agents, patrol the body for infections.  B cells must strike a delicate balance—they need to be highly sensitive to invading viruses while remaining tolerant of self-antigens to prevent autoimmune responses, where the body attacks itself.  As the team found out, B cells harness a special protein called LYN which tunes the signal of activation, like a “controller” in B cells.  When B cells encounter antigens that are freely diffusing like many other proteins in the body, LYN dials up the “resistance” towards activation, because those freely diffusion proteins simply don’t look like viruses at all.  However, when the antigen is displayed on a spherical structure similar to that of a virus, LYN tunes down the “resistance” dramatically so that the B cells get immediately activated, start proliferating and secrete antibodies to attack the virus. 

This activation also kicks off a cascade of events that promote the survival of these B cells in the absence of immediate T cell help, which is critical to amplify the B cells response to the virus.  All of these responses are mediated by the antigens displayed on the surface of a spherical structure, like that of viruses. 

“We are surprised by mother nature’s solution to this important problem,” Cheng said, “but it is a highly elegant mechanism”.  Traditionally, the immune system's response to viruses has been a complex puzzle, but this research has uncovered one crucial piece of the puzzle. “It is work like this being done by our amazing innovative faculty that is working to solve some of our most pressing and challenging health care questions,” said Vicki Ellingrod, Dean University of Michigan College of Pharmacy. 

In addition, the team found that virus-like antigens trigger "all-or-none" B cell responses that are strongly influenced by the antigen density, rather than antigen affinity. The signaling induced by virus-like antigens leads to robust activation.  This enables even small amounts of antigens to significantly induce B cell proliferation in vivo, in the absence of any other adjuvant.  These findings highlight the complexity and efficiency of the immune system's response to viral threats and have extremely important implications for researchers working to develop new effective and safe vaccines and other therapies targeting viral infections.