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Principal Investigator: JEREMY M. BOSS
Organization: EMORY UNIVERSITY
Fiscal Year: 2024
Award: $541,941
Funding agency: National Institute of Allergy and Infectious Diseases
Humoral immunity provides protection from pathogenic viral, bacterial, and parasitic infections and is mediated
by antibodies that are produced following the differentiation of B cells into antibody secreting cells (ASC). Both
T cell independent and dependent processes contribute to the formation of ASC, as well as memory B cells
(MBC); each of which can provide lifelong immunity. Although major transcription factor networks and gene
expression changes that occur when B cells differentiate to ASC have been described, the transcriptional and
epigenetic mechanisms by which B cells adopt an early heritable cell fate program that determines ASC fate
versus one of memory and how initial and recall immune responses are programmed is still largely unknown. As
evidenced by the absolute need to create vaccines and other immune-based therapies to treat emerging
diseases, such as that caused by SARS-CoV2, it is essential that we have a full understanding of the pathways
that control the cell fate choices made by B cells. When stimulated in vivo, mouse naïve B cells undergo eight
cellular divisions as they differentiate to ASC. Each of these divisions is associated with a unique epigenetic
program that orchestrates a distinct transcriptional program providing the structure and machinery to regulate
proliferation, metabolism, stress responses, and pathways that are necessary to form an ASC. We recently
observed that instead of a single pathway arising from in vivo B cell activation, two branches emerged during
early cell divisions. One leads to ASC; whereas the other (termed non-ASC branch) expresses pre-MBC genes,
suggesting that it is the differentiation path to an MBC. Each cell fate path or branch express a unique set of
transcription factors that influence how a B cell will respond to stimulation. Aim 1 will determine which of these
differentially expressed factors contribute to this early decision and determine their regulatory targets that drive
cell fate choice. Aim 1 will also seek to understand the roles played by three epigenetic modifiers (EZH2, UTX
and LSD1) that alter ASC formation and determine how their absence alters B cell fate choices. Little is known
about the cell intrinsic mechanisms (epigenetic and transcriptional programming) that allow MBC to respond to
antigen more quickly. Our data show that MBC have a unique chromatin accessibility profile that suggests that
they can respond more quickly because they are epigenetically preprogrammed to differentiate. Thus, Aim 2
will determine: how memory B cells respond more quickly to antigen rechallenge, rely on the above epigenetic
modifiers to form ASC, and whether they follow the same fate determining choices as naïve cells. This will be
tested in vivo using a series of reporter mice and Cre recombinase-drivers, conditional knockouts for the above
epigenetic modifiers, and epigenomic/transcriptomic assays. Results from our study will provide a molecular
understanding of how B cells respond to antigen and differentiate through multiple pathways leading to immunity
and will provide new clues to how to better develop immune therapeutics and vaccines.
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