Manipulating alpha(v) integrins on B cells to promote lung-resident B cell responses - Project Summary/Abstract Current vaccines against mucosal respiratory viruses, although effective at reducing disease severity, do not provide protection at the respiratory tract, the site of infection, cannot effectively protect against multiple variants of the viruses and do not induce long-lived immune response. Therefore, there is a need to design more effective vaccines that can trigger durable and protective immunity against mucosal respiratory viruses, directly at respiratory sites. However, a major barrier for progress in this area is that the signals that regulate immune responses at respiratory sites remain unclear. Viral infection can induce B cell mediated immune response in the lungs, that result in mucosal antibodies capable of targeting multiple antigenic variants on viruses and long- lived memory B cells. Therefore, our objective in this renewal application is to understand how viral infection elicits long-lived and protective B cell responses in the lungs and design strategies to mimic these therapeutically. Our R01 studies revealed a new mechanism regulating B cell responses in the lungs during viral infection. In previous work, we showed that a family of integrins, αv integrins, expressed on B cells, restrain toll-like receptor (TLR) signaling response of B cells to TLR ligands. TLR ligands are integral components of viral products and mice with deletion of αv from B cells, showed increase in B cell TLR signaling and increase in long-lived protective B cell responses after immunization with viral antigens. In recent R01 studies, we found that this function of αv also regulates long-lived B cell responses locally in the lungs after viral infection. Deletion of B cell αv integrin, in mice (αv-CD19 mice), promoted sustained increase in lung-resident GC and memory B cells, after influenza infection. These B cells can target multiple influenza antigens. Moreover, we find that αv antagonists can also improve B cell responses in mice and in human B cell cultures. Our hypothesis is that blockade αv on B cells, enhances TLR signaling, leading to prolonged GC and memory B cells in the lungs after viral infection. We predict these tissue-resident GC and memory B cells provide long-lived protection against re-infection from multiple influenza variants. Therefore, in Aim1 we will investigate how B cell TLR signaling promotes GC B cell responses in the lungs after infection and whether enhanced TLR signaling can promote similar responses in the lungs after vaccination. In Aim2, we will use αv-knockout mice to establish the capacity of lung-resident GC and memory B cells, to protect from infection and in Aim3 we will ask whether αv antagonists can be used to promote similar beneficial mucosal immune response in mice and human B cell cultures. The proposed work is significant because, it addresses both the mechanisms that promote immunity at the respiratory sites and strategies that could be used to promote these therapeutically. Based on these studies, αv antagonists could be developed to enhance induced tissue-resident immunity. Our approach is innovative as we are leveraging our expertise on B cells and integrin biology to address lower respiratory tract immunity in mice, as well as using human B cell organoid cultures to study mucosal immune response, in human setting.
