Many factors are involved in the superior protection seen in the recall response but our goal here is to define the various roles of two different memory CDS T cell subsets, Tel and Tel 7, in a model of protection against influenza infection and to determine how those roles are executed. These studies will lead to a fuller understanding of the complexity of the memory CDS T cell response and how it protects against disease.
In AIM 1. We will generate mice with only defined subsets of CDS memory cell populations in the absence of any other consequences of antigen priming. We will determine the migratory properties and adhesion molecule and chemokine receptor expression of the subsets. In separate experiments, we will determine the effect of eliminating host T cells before viral challenge to distinguish between direct and indirect effects of memory cells the first step to defining mechanisms. We will generate polarized CDS T cell memory mice specific for epitopes of the Mtb protein, Antigen 85 and Tb10.4, to study the role in Tb in collaboration with Dr. Cooper.
In AIM 2. We will use the models developed in AIM 1 to determine the underlying mechanisms involved in the responses of each subset and will test the following hypotheses as to how each subset protects against lethal challenge. -Tel 7 memory cells enhance the recruitment of host CD4 and/or CDS T cells into the lung following challenge and thus accelerate a beneficial response. We will determine the mechanism of recruitment and will assess the migratory properties and adhesion molecule and chemokine receptor expression of the recruited host cells, in consultation with Dr. Bradley. -Tc17 memory cells enhance the recruitment of host B cells, neutrophils and/or other non-T cells into the lung following challenge. We will analyze what cells are recruited, determine the mechanism of recruitment and whether the recruited cells are beneficial or increase immunopathology -Tel 7 memory cells accelerate the production of B cell clusters and new antibodies (both total and neutralizing) to the challenge virus and lead to earlier viral clearance. We will analyze mechanisms involved. -Tel 7 memory cells enhance repair by accelerating the proliferation of type 2 epithelial cells, repair lung damage and restore lung function, following challenge. We will analyze mechanisms involved. We will collaborate with Dr. Swain to compare the performance of Tc17 and Th17 and determine what role the two subsets have in each of the hypotheses. Are they redundant, synergistic or different?

Public Health Relevance

; Our proposal seeks to understand the nature of the memory T cell subsets and the role that they play in response to pathogens in general and influenza infection in particular. It will thus be possible to tailor vaccine strategies that provide optimal protection. Influenza epidemics causes up to 50,000 deaths per year and 20 million cases of infection, with huge economic loss . The pandemic influenzas of 1SS9, 1901, 1918, 1957, and 1968 caused vastly greater losses and a recurrence of H2N2 or the current bird flu has the potential to cause a similar outbreak sometime in the future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046530-13
Application #
8379741
Study Section
Special Emphasis Panel (ZAI1-CL-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$305,682
Indirect Cost
$68,762
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

Showing the most recent 10 out of 80 publications