""""""""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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046530-13
Application #
8316256
Study Section
Special Emphasis Panel (ZAI1-CL-I (M2))
Program Officer
Chiodetti, Lynda
Project Start
2009-09-22
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
13
Fiscal Year
2012
Total Cost
$1,878,934
Indirect Cost
$422,657
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
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

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