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Principal Investigator: MARK J SHLOMCHIK
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $690,672
Funding agency: National Institute of Allergy and Infectious Diseases
Humoral immune memory is critical for vaccine efficacy and to prevent reinfection. Conversely, dysregulation
of humoral immune memory is a likely culprit in autoimmunity and aging. A critical component of humoral im-
munity is the memory B cell (MBC). MBC generate more robust responses upon pathogen re-exposure, as
well as adapt to mutation-driven shifts in pathogen antigenicity. MBC are challenging to study, as Ag-specific
MBC specific to given immunogens are often quite rare, and therefore hard to track. Yet, to examine intrinsic
changes in MBC, it is important to compare naïve Ag-specific precursors (NBC) to their MBC progeny, control-
ling for cell numbers, which requires specially engineered systems. To surmount these challenges, in previous
cycles of this program, we have created tools and systems to make larger numbers of MBC, ways to track
these cells, and developed transfer systems to test function in vivo as well as engineered genetic strategies to
target MBC and their precursors. Using these tools, we discovered and characterized MBC subsets that have
divergent functions. We have further investigated when and where MBC subsets are formed, delineated differ-
entially expressed genes among NBC and MBC subsets; and, most recently, comprehensively described dif-
ferentially-expressed surface markers in both murine and human MBC. In the current proposal, we leverage
these model systems to investigate the processes that govern MBC generation, the molecular and epigenetic
circuits that control distinct memory B cell states, and the types and functioning of MBC that are made after
repeated antigen exposures. In this regard, we have exciting preliminary data that elucidate the major epige-
netic differences between NBC and MBC and their subsets. We hypothesize that such differential chromatin
imprinting occurs during the precursor activation phase. In Aim 1 we will test this hypothesis, developing ge-
nome-wide epigenetic and associated gene expression maps that will define B cell epigenetic memory and will
also implicate TFs that are important for establishing such networks. In Aim 2, we will systematically investi-
gate a set of prioritized candidate TFs, using inducible Cre mice developed in our lab as well as available
floxed alleles. We will determine the effect of loss of these TFs on both development of key MBC subsets as
well as on their function. Our recent data show that a stem-like MBC subset can undergo exhaustion, and then
fail to regenerate sufficient new stem-like cells. This observation has important implications for humans—
where recurrent pathogen exposure and vaccination are common—and could inform vaccine approaches as
well as partly underlie the original antigenic sin phenomenon. In Aim 3 we will investigate these issues using a
powerful system in which MBC are tracked through multiple cycles of immunization. These Aims address cen-
tral problems in the field—with important translational implications—that we are in a unique position to address.
The work we propose will help define the cell-intrinsic “essence” of B cell memory, with important implications
for vaccine design and our fundamental understanding of the immune state.
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