Producing high-affinity antibodies that potently neutralize target pathogens remains a central goal for vaccine research. Many promising vaccine antigens fail to elicit long-lasting protective antibodies due to inefficient generation of high-affinity memory B cells. While memory B cell development is an active area of research, major gaps remain in our understanding of cognate regulation by CD4+ TH cells and the rules governing ongoing evolution of antigen-specific B cell memory. Research Focus: In these recent studies, we demonstrate that all memory B cell responses require antigen-specific mTH cells. Importantly, direct in situ labeling revealed both Bcl-6+ and Blimp-1+ CD4+ TH cells in the follicular regions of reactive LNs after recall. In support of this observation, using single cell T-qPCR, we demonstrate a transcriptional divide between two tetramer-binding CXCR5+ mTFH compartments with differential expression of Bcl-6 and Prdm-1 at recall. Based on these findings, we propose a division in cognate regulatory function with separable mechanisms used by the different mTFH compartments that may also pre-exist at initial priming. We predict that this division of cognate regulatory function can be targeted to control, remodel and re-assort antigen-specific memory B cell fate at antigen recall with high impact on durable immune protection.
Specific Aims : We have developed multi-dimensional single cell strategies to track complex cellular behaviors in vivo and can temporally delete of these two major transcriptional repressors in a cell- specific manner using mixed BM chimeras. We will use this approach: SA-1: to study the molecular control of antigen-specific mTFH differentiation. SA-2: to dissect and modify the mechanisms and GC-regulating function of Bcl-6+ mTFH cells SA-3: to examine the cognate regulatory mechanisms used by Prdm-1+ mTFH cells. Impact: We use polyclonal murine models of protein vaccination with state-of-the-art single cell analyses of antigen-specific immune function. These high-resolution studies of model antigens have the capacity to shift the basic conceptual framework that surrounds existing vaccine paradigms. Importantly, these basic new principles and assays can be used to re-design contemporary vaccine formulations that optimize high-affinity B cell immunity to more complex antigens.
Vaccines rely on antibodies to protect us for long periods against infection. We know a lot about how antibody molecules function but very little about the memory cells that quality control their production. In order to design better vaccines, we need to understand how memory T cells work to improve the quality of antibody produced at the vaccine boost.
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| 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 |
| 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 |
| Malherbe, Laurent; Mark, Linda; Fazilleau, Nicolas et al. (2008) Vaccine adjuvants alter TCR-based selection thresholds. Immunity 28:698-709 |
| Fazilleau, Nicolas; Eisenbraun, Michael D; Malherbe, Laurent et al. (2007) Lymphoid reservoirs of antigen-specific memory T helper cells. Nat Immunol 8:753-61 |
| McHeyzer-Williams, Louise J; McHeyzer-Williams, Michael G (2004) Developmentally distinct Th cells control plasma cell production in vivo. Immunity 20:231-42 |
| Malherbe, Laurent; Hausl, Christina; Teyton, Luc et al. (2004) Clonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity 21:669-79 |
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