"Generation and Function." We propose an integrated program to analyze CD4 and CD8 T cell memory against the respiratory pathogens causing influenza (flu) and tuberculosis (TB). In sophisticated animal models, we will define subsets of CD4 and CD8 memory T cells and determine the cellular and molecular basis of their generation, functions, location, persistence and relationship to other T cell subsets. This will greatly extend our basic understanding of immunity. "Generation and Persistence of CD4 Memory Subsets" (Swain), will determine the relationships of different functional subsets of CD4 T cells and will determine if they become functionally committed subsets of memory and define their protective functions. They will separate subsets of effector and memory CD4 T cells that work by killing infected targets and compare them to those that cause inflammation and secrete an inflammatory factor IL-17, and those that act by helping B cells. "CD8 Memory T Cells Mechanisms of Protection" (Dutton) will identify the mechanisms used by the CD8 T cell subsets that parallel those in Project 1 for CD4 subsets. In particular they will study the IL-17 producing subset of CD8 T cells that their preliminary data show plays a key role in protection against influenza, and compare these Tc17 to Tc1 subsets and define their function and protective abilities and mechanisms of action. "Regulation Of T Cell Homeostasis and Memory" (Bradley), will determine whether signals from "selectins" expressed on lung cells control CD4 and CD8 T cell responses and are needed for the development and persistence of CD4 memory cells. They will determine if selectin binding capacity identifies a distinct functional subset of CD4 cells, and what CD4 responses are selectin-dependent. "T Cell Memory to TB in the Lung" (Cooper), will determine factors that regulate induction of protective memory CD4 T cells, especially of the Th17 subset. They will also examine factors in the lung that regulate expression of memory T cell function in the lung and determine whether modulating the IL-17 memory response in the lung can increase protection. Defining the mechanisms by which memory T cell subsets provide protective immunity, is likely to result in identification of new correlates of protection for flu and TB, that will inform future vaccines targeted towards inducing robust T cell memory in addition to antibody, so that immunization will be effective even when new strains of TB and flu, including pandemic flu, emerge.
We believe that identifying the T cell subsets that contribute to protection and by defining mechanisms that regulate their generation and persistence, novel insights relevant to new strategies for improved vaccines will be obtained.
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|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|
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|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, EgÃdio; Carmona, Jenny et al. (2015) BCG vaccination-induced long-lasting control of Mycobacterium tuberculosis correlates with the accumulation of a novel population of CD4âºIL-17âºTNFâºIL-2âº T cells. Vaccine 33:85-91|
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|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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