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
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
Torrado, Egidio; Fountain, Jeffrey J; Robinson, Richard T et al. (2013) Differential and site specific impact of B cells in the protective immune response to Mycobacterium tuberculosis in the mouse. PLoS One 8:e61681
Hamada, Hiromasa; Bassity, Elizabeth; Flies, Amanda et al. (2013) Multiple redundant effector mechanisms of CD8+ T cells protect against influenza infection. J Immunol 190:296-306
Torrado, Egidio; Cooper, Andrea M (2013) Cytokines in the balance of protection and pathology during mycobacterial infections. Adv Exp Med Biol 783:121-40
McKinstry, K Kai; Dutton, Richard W; Swain, Susan L et al. (2013) Memory CD4 T cell-mediated immunity against influenza A virus: more than a little helpful. Arch Immunol Ther Exp (Warsz) 61:341-53
Brown, Deborah M; Lee, Sarah; Garcia-Hernandez, Maria de la Luz et al. (2012) Multifunctional CD4 cells expressing gamma interferon and perforin mediate protection against lethal influenza virus infection. J Virol 86:6792-803
Torrado, Egidio; Cooper, Andrea M (2011) What do we really know about how CD4 T cells control Mycobacterium tuberculosis? PLoS Pathog 7:e1002196
Torrado, Egidio; Robinson, Richard T; Cooper, Andrea M (2011) Cellular response to mycobacteria: balancing protection and pathology. Trends Immunol 32:66-72
McKinstry, K K; Strutt, T M; Swain, S L (2011) Hallmarks of CD4 T cell immunity against influenza. J Intern Med 269:507-18
Cooper, A M; Mayer-Barber, K D; Sher, A (2011) Role of innate cytokines in mycobacterial infection. Mucosal Immunol 4:252-60

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