B cell memory is a multi-faceted cellular process whose main purpose is long-term immune protection targeted to previously experienced antigens. While humoral immunity is considered the most substantial barrier to antigen re-challenge, the cellular underpinnings of this important protective mechanism remain poorly understood. My laboratory focuses on helper T (Th) cell- regulated B cell immunity and seeks to understand the cellular and molecular mechanisms that regulate the development of antigen-specific B cell memory in vivo. We hypothesize that B cell memory is organized into multiple cellular compartments, developmentally distinct and functionally sub-specialized to provide long-term antigen-specific protection. During the initial funding period, we provided evidence for two separable compartments of antigen- specific memory B cells based on antigen-binding, isotype-switch, BCR expression, BCR co- receptor expression (CD79b), differential cell surface phenotype, cellular dynamics in vivo, presence of mutated mRNA for Ig genes and adoptive transfer of antigen responsiveness. These data allowed us to propose a linear progression of development for antigen-specific B cell memory. This model suggests that germinal centers export 'post-GC'6B2+ CD79b+ memory B cells that give rise to distinct and persistent 'pre-plasma'6B2neg CD79b+ memory B cells, the cellular precursors of CD138+ long-lived plasma cells (PC). The developmental defect in 6B2neg CD79b+ memory compartment and loss of CD138+ plasma cells in mice with a conditional deletion of Blimp-1 was consistent with this model. We will pursue these studies across two specific aims to determine unambiguously the origins of the memory B cell subsets (SA#1) and to examine what mechanisms regulate their development, survival and reactivation in vivo (SA#2).
| McHeyzer-Williams, Louise J; Dufaud, Chad; McHeyzer-Williams, Michael G (2018) Do Memory B Cells Form Secondary Germinal Centers? Impact of Antibody Class and Quality of Memory T-Cell Help at Recall. Cold Spring Harb Perspect Biol 10: |
| Dufaud, Chad R; McHeyzer-Williams, Louise J; McHeyzer-Williams, Michael G (2017) Deconstructing the germinal center, one cell at a time. Curr Opin Immunol 45:112-118 |
| McHeyzer-Williams, Louise J; Milpied, Pierre J; Okitsu, Shinji L et al. (2015) Class-switched memory B cells remodel BCRs within secondary germinal centers. Nat Immunol 16:296-305 |
| Wang, Nathaniel S; McHeyzer-Williams, Louise J; Okitsu, Shinji L et al. (2012) Divergent transcriptional programming of class-specific B cell memory by T-bet and RORýý. Nat Immunol 13:604-11 |
| McHeyzer-Williams, Michael; Okitsu, Shinji; Wang, Nathaniel et al. (2012) Molecular programming of B cell memory. Nat Rev Immunol 12:24-34 |
| Pelletier, Nadége; McHeyzer-Williams, Louise J; Wong, Kurt A et al. (2010) Plasma cells negatively regulate the follicular helper T cell program. Nat Immunol 11:1110-8 |
| McHeyzer-Williams, Louise J; Pelletier, Nadege; Mark, Linda et al. (2009) Follicular helper T cells as cognate regulators of B cell immunity. Curr Opin Immunol 21:266-73 |
| Todd, Derrick J; McHeyzer-Williams, Louise J; Kowal, Czeslawa et al. (2009) XBP1 governs late events in plasma cell differentiation and is not required for antigen-specific memory B cell development. J Exp Med 206:2151-9 |
| Fazilleau, Nicolas; Mark, Linda; McHeyzer-Williams, Louise J et al. (2009) Follicular helper T cells: lineage and location. Immunity 30:324-35 |
| Fazilleau, Nicolas; McHeyzer-Williams, Louise J; Rosen, Hugh et al. (2009) The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding. Nat Immunol 10:375-84 |
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