Vaccine development is a critical health care initiative and the development of immunological memory is key to the efficacy of candidate vaccines. To be effective, a vaccine needs to induce, not only a good immune response, but also long-term protective immunity., which is mediated by antigen specific effector and memory T cells. As a population, memory T-cells respond more rapidly to secondary challenge with antigen and are believed to have cellular and molecular characteristics that are distinguishable from effector TH cells. The objective of this proposal is to characterize the development of antigen specific memory TH cells in an experimental mouse model of TH cell immunity. A better understanding of the cellular and molecular basis of memory TH cell development in vivo will provide the means to augment, specifically modify and better direct vaccine-induced immunity. Antigen-specific TH cells have been very difficult to study in normal animals. Primarily, this is due to the extremely low numbers of TH cells that are specific for any one antigen. While it is possible to isolate populations of cells that contain an antigen specific component, these populations are not pure and still contain other cells that confound the unambiguous assay of function. To further complicate analysis, these regulators of the immune response also exert regulatory effects on each other. Therefore, it is imperative to first purify the specific cells of interest and them analyze them at a single cell level. While the antigen specific population may be pure, the individual cells within the population will be heterogeneous with respect to function. In the current study using multi-parameter flow cytometry and gene amplification of T-cell receptors from single cells, it is possible to purify individual antigen specific TH cells and molecularly characterize their specificity directly at the single cell level. They plan to analyze the development of TCR repertoire and relate structure to function to ascertain the biochemical basis for clonal selection in the helper T-cell compartment. They will assess what regulates cytokine production by helper T-cells in vivo. Next, they will probe the molecular basis for cell death and long-term survival in the emergence of effector cell function and memory cell generation. In the last aim, they will use in vitro assays to reveal changes in the molecular physiology of antigen specific helper T cells to understand more clearly the mechanisms that underpin memory cell differentiation. By comparative analysis of antigen specific primary effector cells, resting memory cells and memory effector cells, they will further understand the cellular and molecular dynamics of these regulators of protective immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI040215-03
Application #
2887271
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Quill, Helen R
Project Start
1996-09-30
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Duke University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
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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