Effective vaccines exist for many pathogens. But rational design methods have failed to generate vaccines against many important pathogens. Importantly, our understanding of the molecular pathways involved in generating long-lived and broadly protective immunity is incomplete. Using a newly discovered molecule, this application is directed at understanding pathways that regulate the ability of B cells to provide durable and cross-protective antibody responses. We have discovered that the transcription factor Zbtb20 is required for maintenance of long lived plasma cells, with only high affinity clones persisting afte immunization. These findings provide us with the unique opportunity to: 1) Identify the signaling and survival pathways that regulate plasma cell diversity and lifespan through genetic complementation experiments;2) Determine the function of low and moderate affinity antibodies in cross-protection against viruses and in the pathogenesis of autoimmunity.
The length of time that antibodies persist after vaccination and infection and the efficacy of these antibodies against related pathogens varies widely. The goal of this proposal is to identify and manipulate the molecular mechanisms that regulate both the duration and cross-reactivity of antibody responses after vaccination.
|Chou, Chun; Verbaro, Daniel J; Tonc, Elena et al. (2016) The Transcription Factor AP4 Mediates Resolution of Chronic Viral Infection through Amplification of Germinal Center B Cell Responses. Immunity 45:570-82|
|Jash, Arijita; Wang, Yinan; Weisel, Florian J et al. (2016) ZBTB32 Restricts the Duration of Memory B Cell Recall Responses. J Immunol 197:1159-68|
|Lam, Wing Y; Becker, Amy M; Kennerly, Krista M et al. (2016) Mitochondrial Pyruvate Import Promotes Long-Term Survival of Antibody-Secreting Plasma Cells. Immunity 45:60-73|
|Chan, S R; Rickert, C G; Vermi, W et al. (2014) Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ER*(+) tumorigenesis. Cell Death Differ 21:234-46|
|Wang, Yinan; Bhattacharya, Deepta (2014) Adjuvant-specific regulation of long-term antibody responses by ZBTB20. J Exp Med 211:841-56|