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?
; 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.
|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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