Our collaborative effort will be aimed at combining cellular and molecular approaches to study the factors that are required for the optimum development of long-lasting T cell memory to influenza virus and M. tuberculosis. Induction of such memory is the key goal of vaccination, but the pathways leading to and factors regulating memory development are poorly understood. Knowledge of the basic processes involved will yield important insights that can be exploited therapeutically and used to increase the efficacy of immunization. Disease from influenza infection ranges from mild to lethal, depending on the level of strain-specific antibody protection afforded by prior exposure to virus. Devastating epidemics have occurred when new viral strains have emerged carrying new hemagglutinin proteins distinct from those to which the population has been exposed. Such strains could also be produced by genetic engineering. Fortunately, T cell responses are not restricted to the variable epitopes and a vaccine strategy focusing on T cell immunity might provide protection to all or most potential strains and/or augment host responses sufficiently to prevent the worst consequences of a pandemic. Tuberculosis is one of the leading causes of morbidity and mortality in the world and is the leading cause of death as a result of an infectious agent. Although drug treatment is available its long duration leads to non-compliance and the subsequent generation of drug resistant strains. For the past 80 years an attenuated vaccine strain has been available however it is of variable efficacy and its use within a population fails to result in eradication of disease. Our studies will identify the kinds of memory CD4 and CD8 T cells immunity required for protection and determine factors that regulate the generation and persistence of those cells. Projects: 1. Regulation of CD4 Memory Cell Development and Persistence (Swain) will identify memory CD4 subsets in response to influenza, determine which are protective, how protective memory is generated and what regulates persistence. 2. Characterization of Influenza-Specific CD8 Memory (Dutton) will ask similar question for protective CD8 memory in influenza. Together Projects 1 and 2 will compare CD4 Vs CD8 immunity to influenza. 3. Regulation of Memory T Cell Recruitment and Responses in the Lung. (Bradley) will determine the mechanisms, which determine the recruitment of CD4 and CD8 T cells to the lung following influenza infection and will determine the responses of these cells in the lung. 4. Expression of T cell memory in the TB infected lung. (Cooper) will determine how memory responses to TB are induced, how they are recruited to the lung and whether they provide long-term protection against pulmonary TB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046530-08
Application #
7046774
Study Section
Special Emphasis Panel (ZAI1-PTM-I (M1))
Program Officer
Chiodetti, Lynda
Project Start
1999-09-30
Project End
2008-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
8
Fiscal Year
2006
Total Cost
$1,880,848
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
020658969
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
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Strutt, T M; Dhume, K; Finn, C M et al. (2018) IL-15 supports the generation of protective lung-resident memory CD4 T cells. Mucosal Immunol 11:668-680
Devarajan, Priyadharshini; Jones, Michael C; Kugler-Umana, Olivia et al. (2018) Pathogen Recognition by CD4 Effectors Drives Key Effector and Most Memory Cell Generation Against Respiratory Virus. Front Immunol 9:596
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Swain, Susan L; Kugler-Umana, Olivia; Kuang, Yi et al. (2017) The properties of the unique age-associated B cell subset reveal a shift in strategy of immune response with age. Cell Immunol 321:52-60
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
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
Cruz, Andrea; Torrado, EgĂ­dio; 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
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

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