The germinal center (GC) is a primary source of long-lived memory B and plasma cells (PCs). Affinity maturation, somatic mutation, and generation of intraclonal diversity are all key processes that occur in the GC, with the net result dramatically affecting humoral immunity to both pathogens and vaccines. Despite recent progress, the mechanisms behind central processes including selection for higher affinity, selection against self-reactivity, and control of decisions to differentiate into memory or PC lineages remain unresolved. This proposal focuses on selection and signaling in the GC. Recently, during investigations of B cell receptor (BCR) function in the GC, we were surprised to find that classical BCR signal transduction was all but extinguished in the vast majority of GC B cells (GCBC). This was in large part mediated by increased functional phosphatase activity. However, we found that GCBC were relieved of suppression and able to signal again when reaching the G2 phase of cell cycle. These findings not only provided fresh insights into how Ag might guide the fate of B cells in the GC, they also highlighted how little we yet know about BCR signaling and function during physiologic immune responses and in cell types other than nave B cells. In particular, GCBC massively remodel gene expression and these shifts combined with many post-transcriptional/translation alterations could greatly influence signaling pathways and outcomes. We are now in a position to more deeply elucidate the extent and nature of BCR signaling in the GC and to understand the implications and mechanisms of GC B cell selection. Here we propose to further explore and define BCR signaling in the GC. These studies will inform our understanding of both BCR signaling and GC biology at a basic level. Through this work, we hope to link molecular events in the GCBC with functional outcomes, with the long-term goal of developing a detailed understanding of selection at both the molecular and cellular levels. We will pursue this long-term goal via three Aims. The first is focused on defining the limits and parameters of inactivation of BCR signal transduction in the GC, as well as in non-GC activated B cells. The second seeks to understand how selection works by testing the outcome of BCR and T cell signals on GCBC.
The final aim tests hypotheses about GCBC signaling per se, with a goal of beginning to elucidate how GC BCR signaling is rewired compared to nave B cells.

Public Health Relevance

The immune system displays 'memory'-a faster and better response-which makes an individual resistant to infection after vaccination or after an initial infection. This memory is formed in a structure called the germinal center, which is elicited after immunization. This proposal seeks to understand in more detail how the germinal center forms the faster and better cells that enable immune system memory.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Ferguson, Stacy E
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University of Pittsburgh
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