Memory T cells are important for protection against repeat exposures to infectious agents. In man, how memory T cells are generated or maintained during the adult years, and how the number and type of T cell changes with pathogen re-exposure are still poorly understood. We address these issues in a detailed manner in this proposal. The initial system we will investigate is the memory response of cytotoxic T cells to influenza matrix protein restricted by the HLA-A2 molecule. We have shown that the memory T cells comprise a diverse repertoire constituted of a large number of T cells and their progeny. These T cells all use the same T cell receptor (TCR) beta-chain gene and show a conserved amino acid sequence in the CDR3. The repertoire is composed of many T cells that are present at low numbers and a few that are present at higher frequencies. Our hypothesis is that robust memory T cell repertoires are complex and this complexity results from the manner in which the repertoire is selected. The experiments proposed in this Project benefit directly from the Sampling Core providing PBMC from HLA-A2 blood donors at multiple times. We propose the following Aims: 1. Analyze the response to influenza M1 + HLA-A2 across two cohorts of blood donors, all aged 36-50, all age groups in the HLA typed donor pool. This will provide a description of repertoire diversity across a population of individuals. 2. Test the ability of the adult memory repertoire to respond to related antigenic peptide. This tests the hypothesis that a robust system will be able to recognize related antigens that result from an attempt at viral evasion or infection with a related virus. 3. Perform longitudinal analyses on a subset of the donor pool, correlating changes with risk of exposure to influenza. These studies should show how the repertoire changes with re-exposure to pathogen 4. Determine to what extent conclusions reached are a general phenomenon by testing another influenza-derived HLA-A2 restricted peptide and an influenza derived peptide restricted by a different HLA molecule, in this case HLA-A11. The completion of these aims should provide us with a detailed quantitative and qualitative description of how robust memory T cells are maintained in adults and how they change with antigen exposure. This should lead to a better understanding of how memory T cells evolve and how they may be fostered.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI062627-02
Application #
7116229
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$461,982
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
Alarcon Falconi, T M; Cruz, M S; Naumova, E N (2018) The shift in seasonality of legionellosis in the USA. Epidemiol Infect 146:1824-1833
Yassai, Maryam B; Demos, Wendy; Gorski, Jack (2017) Structural and Mechanistic Implications of Rearrangement Frequencies within Human TCRBV Genes. J Immunol 199:1142-1152
Gil, Anna; Yassai, Maryam B; Naumov, Yuri N et al. (2015) Narrowing of human influenza A virus-specific T cell receptor ? and ? repertoires with increasing age. J Virol 89:4102-16
Zhou, Vivian; Yassai, Maryam B; Regunathan, Jeyarani et al. (2013) The functional CD8 T cell memory recall repertoire responding to the influenza A M1(58-66) epitope is polyclonal and shows a complex clonotype distribution. Hum Immunol 74:809-17
Bonacci, Benedetta; Edwards, Brandon; Jia, Shuang et al. (2012) Requirements for growth and IL-10 expression of highly purified human T regulatory cells. J Clin Immunol 32:1118-28
Kumar, Pawan; Bartoszek, Allison E; Moran, Thomas M et al. (2012) High-throughput detection method for influenza virus. J Vis Exp :
Levy, H; Wang, X; Kaldunski, M et al. (2012) Transcriptional signatures as a disease-specific and predictive inflammatory biomarker for type 1 diabetes. Genes Immun 13:593-604
Petrova, Galina; Ferrante, Andrea; Gorski, Jack (2012) Cross-reactivity of T cells and its role in the immune system. Crit Rev Immunol 32:349-72
Petrova, Galina V; Gorski, Jack (2012) Cross-reactive responses to modified M1??-?? peptides by CD8? T cells that use noncanonical BV genes can describe unknown repertoires. Eur J Immunol 42:3001-8
Baumgartner, Christina K; Yagita, Hideo; Malherbe, Laurent P (2012) A TCR affinity threshold regulates memory CD4 T cell differentiation following vaccination. J Immunol 189:2309-17

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