Alpha(v) integrins and germinal center B cell responses to viruses

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Project Summary/Abstract A better understanding of immune signaling mechanisms triggered by various types of antigens is critical for development of more effective vaccines against current and emerging pathogens. Our long-term goal is to understand how B cells integrate signals from antigens and their environment to produce effective immunity against pathogens while maintaining tolerance to self-derived antigens. The objective in this application is to determine the mechanisms by which a family of adhesion molecules, αv integrins and autophagy proteins regulate germinal center (GC) B cell processing of viral antigens and development of effective immunity to Influenza virus. In published work, we have shown that αvβ3 heterodimer from the αv family, engages components of the autophagy pathway, to limit TLR signaling in GC B cells, during response to viral antigens containing TLR ligands. As a result, αv-CD19 mice, lacking αv on B cells show increase in key features of GC-mediated antibody response such as affinity maturation, generation of memory B cells and long-lived plasma cells, upon immunization with virus like particles or Influenza virus. Moreover, these mice develop increased cross-reactive antibodies against multiple influenza virus strains after immunization with one strain and also develop better cross-protective immunity to heterosubtypic strains. αv- CD19 mice also develop increased autoantibodies with age, and we propose that αv-mediated regulation of TLR signaling is a mechanism that limits excessive B cell responses to self-antigens. Our central hypothesis for this grant, is that the αv-autophagy pathway also regulates endosomal processing of antigens containing TLR ligands, that are derived from viruses, and limits GC B cell activation by these antigens. Removal of this control from B cells, enhances GC B cell TLR signaling and GC-mediated generation of antibodies reactive against multiple strains of viruses leading to better cross-protective immunity. In this grant we propose to: (1) Determine the mechanism by which augmenting GC reactions by removal of αv-autophagy pathway leads to better cross- protective immunity to influenza virus strains; (2) Determine whether we can use pharmacological targeting of this pathway to manipulate immune responses to influenza virus; and (3) Determine how viral antigens get processed by GC B cells and how αv-autophagy pathway alter this process. Our rationale for this proposal is that a better understanding of new pathways regulating GC B cell activation by viral antigens will allow us to develop much needed vaccination strategies for generation of effective anti-viral immunity. The proposed work is significant because it addresses the mechanisms of how GC B cell activation affects broadly protective anti-viral immunity, which is essential to understand for developing better vaccines. Moreover, based on these studies, αv antagonists could be used to design vaccine adjuvants that provide long-term protection against wide variety of Influenza virus strains. Our approach is innovative as we are using a unique mouse model of enhanced B cell TLR signaling to investigate a novel TLR-αv-autophagy pathway.