The TCR and Transgenic Mouse Development Core will use our expertise in creating animal models of CD4 T cells and human disease to develop state of the art systems to study the role of CD4 T cells during viral infections and detrimental immune-mediated pathology. Core 0 will have several objectives. First, in collaboration with Dr. Welsh, Project 1, we will determine the role of TCR-pMHC affinity in provoking activated CD4 T cells to be targeted by NK cells. With Dr. Swain, Project 2, we will produce and characterize a panel of CD4 T cells specific for influenza A (lAV). These T cells will be used to understand which CD4 T cells are activated during anti-viral immunity, and will also be used with Dr. Stern, Core B to identify novel viral epitopes and to aid in the development of virus-specific pMHC class II tetramers. lAV specific TCRs will be cloned and a novel set of transgenic mice expressing anti-viral TCRs will be created. These new virus-specific TCR Tg mice will be used by Projects 1, 2, and 3 to study anti-viral T cell responses. In collaboration with Dr. Swain and Dr Stern, we will evaluate the role of TCfR-pMIHC affinity in CD4 T cell lineage differentiation and function following lAV infection. We have extensive experience generating T cell hybridomas, cloning TCRs and producing TCR Tg mice. Additional experiments with Dr. Selin, Project 3, will identify mechanisms that cause of cross-reactive CDS T cells to become pathogenic. Experiments with Dr. Selin and Dr. Stern, Projects 3 and 4, will use our- TCR cloning methods and T cell expression systems to characterize human TCRs specific for lAV and HHV-6. The final objective of Core C is to minimize duplicate breeding programs by centralizing the breeding of TCR Tg mice.

Public Health Relevance

The T cell/TCR Core will provide essential molecular biology services to all of the Projects of the Program regarding the production of virus-specific T cell hybridomas, the cloning and characterization ofthe TCRs expressed on these T cell hybridomas. In addition, the Core will generate novel TCR Tg mice and maintain these and additional virus-specific TCR Tg mice used by all of the members of the Program. The services to be provided by the Core will be available to all Project Laboratories, and the Core will also be responsible for training personnel to perform assays.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109858-01
Application #
8665109
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$230,238
Indirect Cost
$92,508
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Urban, Stina L; Berg, Leslie J; Welsh, Raymond M (2016) Type 1 interferon licenses naïve CD8 T cells to mediate anti-viral cytotoxicity. Virology 493:52-9
Bautista, Bianca L; Devarajan, Priyadharshini; McKinstry, K Kai et al. (2016) Short-Lived Antigen Recognition but Not Viral Infection at a Defined Checkpoint Programs Effector CD4 T Cells To Become Protective Memory. J Immunol 197:3936-3949
Stadinski, Brian D; Shekhar, Karthik; Gómez-Touriño, Iria et al. (2016) Hydrophobic CDR3 residues promote the development of self-reactive T cells. Nat Immunol 17:946-55
Zhou, Xin; Hopkins, Jacob W; Wang, Chongkai et al. (2016) IL-2 and IL-6 cooperate to enhance the generation of influenza-specific CD8 T cells responding to live influenza virus in aged mice and humans. Oncotarget 7:39171-39183
Stadinski, Brian D; Obst, Reinhard; Huseby, Eric S (2016) A ""hotspot"" for autoimmune T cells in type 1 diabetes. J Clin Invest 126:2040-2
Fonseca, Jairo Andres; Cabrera-Mora, Monica; Singh, Balwan et al. (2016) A chimeric protein-based malaria vaccine candidate induces robust T cell responses against Plasmodium vivax MSP119. Sci Rep 6:34527
Che, Jenny W; Daniels, Keith A; Selin, Liisa K et al. (2016) Heterologous immunity and persistent murine cytomegalovirus infection. J Virol :
Strutt, Tara M; McKinstry, Karl Kai; Kuang, Yi et al. (2016) Direct IL-6 Signals Maximize Protective Secondary CD4 T Cell Responses against Influenza. J Immunol 197:3260-3270
Wyss, Lena; Stadinski, Brian D; King, Carolyn G et al. (2016) Affinity for self antigen selects Treg cells with distinct functional properties. Nat Immunol 17:1093-101
Devarajan, Priyadharshini; Bautista, Bianca; Vong, Allen M et al. (2016) New Insights into the Generation of CD4 Memory May Shape Future Vaccine Strategies for Influenza. Front Immunol 7:136

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