The central theme of this program project is the determination of the mechanisms by which distinct subsets of memory CD4 T cells provide protective memory against pulmonary infections, with particular emphasis on Thi and Th17 subsets generated during influenza virus or Mycobacterium tuberculosis infections. Proiect 1 (Dr. Swain) will study how distinct helper subsets of CD4 effectors progress to form protective CD4 memory T cell populations in response to immunization or infection with influenza viruses. Proiect 2 (Dr. Dutton) will study how distinct cytotoxic subsets of CD8 effectors progress to form protective Cb8 memory T cell populations in response to immunization or infection with influenza viruses. Proiect 3 (Dr. Bradley) will examine the role CD4 T cell migration plays in the generation and protective function of anti-viral CD4 memory T cell subsets. Finally, Proiect 4 (Dr. Cooper) will investigate the relationship between CD4 T cell subsets in generating protective CD4 memory T cells against MTb. This program as a whole is designed to determine the mechanisms involved in generating protective T cell immunity to pulmonary pathogens, with a strong focus on defining distinct T cell subsets that correlate cytokine polarization profiles with protective functions like migration to the site of infection, cytotoxicity of infected cells, and B cell helper activities. Although each project will approach this question differently, and will address different aspects of CD4 T cell immune responses to pathogen-derived antigens, the goal of this Core is to produce the reagents, viruses, and mouse strains required by the investigators to complete the proposed studies in a well controlled and cost effective manner. Each of the projects in this Program propose experiments that will require polarizing cytokines, monoclonal antibodies, and/or fusion proteins produced by Core B. The projects of Swain, Dutton, and Bradley propose to use influenza viruses, as well as all of the recombinant and purified influenza virus proteins produced by Core B. The projects of Drs. Swain and Bradley would be greatly facilitated with the generation of a flu-specific TCR Tg CD4 mouse strain on the C57BL/6 background.

Public Health Relevance

The goal of Core B is to produce the high quality and critical reagents, viruses, and mouse strains that will facilitate the success of all principal investigators involved in this program.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046530-14
Application #
8526352
Study Section
Special Emphasis Panel (ZAI1-CL-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
14
Fiscal Year
2013
Total Cost
$80,530
Indirect Cost
$17,517
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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
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
Tinoco, Roberto; Carrette, Florent; Barraza, Monique L et al. (2016) PSGL-1 Is an Immune Checkpoint Regulator that Promotes T Cell Exhaustion. Immunity 44:1190-203
Brodeur, Tia Y; Robidoux, Tara E; Weinstein, Jason S et al. (2015) IL-21 Promotes Pulmonary Fibrosis through the Induction of Profibrotic CD8+ T Cells. J Immunol 195:5251-60
Torrado, Egidio; Fountain, Jeffrey J; Liao, Mingfeng et al. (2015) Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection. J Exp Med 212:1449-63
Cooper, Andrea M (2015) Mouse model of tuberculosis. Cold Spring Harb Perspect Med 5:a018556
Cruz, Andrea; Torrado, Egídio; Carmona, Jenny et al. (2015) BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4⁺IL-17⁺TNF⁺IL-2⁺ T cells. Vaccine 33:85-91
Sell, Stewart; Guest, Ian; McKinstry, K Kai et al. (2014) Intraepithelial T-cell cytotoxicity, induced bronchus-associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. Viral Immunol 27:484-96
McKinstry, K Kai; Strutt, Tara M; Bautista, Bianca et al. (2014) Effector CD4 T-cell transition to memory requires late cognate interactions that induce autocrine IL-2. Nat Commun 5:5377
Jain, Nitya; Miu, Bing; Jiang, Jian-kang et al. (2013) CD28 and ITK signals regulate autoreactive T cell trafficking. Nat Med 19:1632-7

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