Protein vaccination is an effective public health initiative with demonstrable utility in the prevention of infectious. An effective immune response to protein antigen relies on the helper T cell regulated development of high-affinity B cell memory and its consolidation after the vaccine boost. The cognate control of B cell immunity requires a spectrum of specialized effector Th cell functions that are temporally and spatially separated in vivo, the subsequent development of antigen-specific Th cell memory and the regulated re-activation of B cell memory responses. Clonal selection underpins the evolution of adaptive immunity in the Th cell and B cell compartment. Our recent studies indicate a unique set of rules for antigen- specific Th cells that control clonal recruitment and cellular expansion in vivo. Sequential selection events based on TCR-pMHCII affinity thresholds shape TCR diversity and regulate clonal dominance in the Th cell compartment. We hypothesize that the differential strength of TCR recognition is also a major determinant in priming effector Th cell function, shaping the memory Th cell compartment and re-shaping the memory response to antigen recall. We will determine the how TCR recognition controls evolution of effector cell evolution and function over the primary response to protein vaccination (SA1). We will then examine the impact of TCR recognition on the development of antigen-specific Th cell memory and the capacity of memory Th cells to respond to antigen recall. Over the course of these studies, we will provide fundamental new insights into the mechanisms controlling adaptive immunity and help to define the best means to obtain long-lasting high affinity B cell immunity to protein antigens. Protein vaccination is an important and effective preventative public health initiative. Vaccinating against sub-components of pathogens is a safe approach to vaccine design. However, we still don't fully understand how the immune system responds to these challenges and how the system develops a memory for what its seen. Our work seeks to understand how the system works in order to design better vaccine that promote stronger, longer lasting protective immune memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040215-15
Application #
8131744
Study Section
Special Emphasis Panel (ZRG1-IMM-E (02))
Program Officer
Lapham, Cheryl K
Project Start
1996-09-30
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
15
Fiscal Year
2011
Total Cost
$390,589
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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
Pelletier, Nad├ęge; 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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