T Cell Memory Generation and Function: Our strategy in this program is to apply the knowledge acquired in recent years to directly investigate the basic biology of immune memory. These advances include, new understandings of the mechanisms of lymphocyte recognition, antigen presentation, lymphocyte activation and programmed cell death. We will make use of new tools to approach important questions about memory T cells including; T cell receptor transgenic mice and mice deficient in lymphocyte subsets or in molecules involved in immune responses (knockout mice) and ne adoptive transfer models of lymphocyte response as well as methods to visualize T cells in situ. We have characterized CD4 and CD8 T memory cells and have developed in vitro and in vivo models in which their generation can be assessed and their in vivo migration visualized. We will determine the factors which are required for CD4 and CD8 memory T cell generation, persistence and migration. Project 1: Regulation of CD4 T Cell Memory Development and Function (Swain) will focus on the factors necessary for the generation of CD4 memory. This will be determined both by manipulating the in vitro generation of activated CD4 T cells to a pre-memory state, where transfer to adoptive hosts in the absence of antigen results in memory formation and by examining the host factors required for the transition from pre- memory to memory. The roles of antigen-stimulation, key cytokines and co-stimulatory interactions, chemokines and adhesion molecules will be determined and the mechanisms responsible for each step examined. With Project 2, we will directly compare the requirements of CD4 and CD8 cells and we will collaborate with Project 3 to examine the role of these same factors in memory CD4 T cell migration. Project 2: Regulation of CD8 T Cell Memory Generation (Dutton) will focus on the factors necessary for the generation of CD8 memory examining the roles of antigen dose and duration, co-stimulatory interactions and growth and survival cytokines for their ability to generate pre-memory cells and for the transition in vivo from pre-memory and memory cells. The possibility that there is a distinct memory precursor cell will be investigated. The nature and function of CD8 memory cells will be determined. Direct comparison of CD4 and CD8 memory generation will be done in collaboration with Project 1 and the roles of the different factors in CD8 memory T cell migration will be done as a collaboration with Project 3. Project 3: Memory T Cell Migration (Bradley), will concentrate on in vivo studies addressing the molecular interactions that regulate memory lymphocytes go and how they get there. These studies will include evaluations of efficient protocols for generating memory in immunological sites where it is needed. The studies will determine the roles of antigen, of cytokines, of adhesion molecules and of chemokines in regulating memory T cell migration following antigen stimulation. The project will collaborate with Projects 1 and 2 to determine whether CD4 and CD8 memory populations generated under different conditions have distinct pathways of migration and distinct mechanism. Together these studies will provide a comprehensive picture of some of the most important aspects of regulating the development of memory including the roles of specific antigen and the interactions of the specific lymphocytes with one another, with other regulatory cells such as antigen-presenting cells and with their milieu. By combining their expertise and exchanging their findings the investigators will be able to capitalize on each other's observations and importantly, design joint experiments which would not otherwise be feasible. We believe these studies will pinpoint aspects of memory generation that will provide the basis for rational vaccine development and for intervention in the immunization process with the potential to considerably enhance the efficacy of immunization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
1P01AI046530-01
Application #
6031545
Study Section
Special Emphasis Panel (ZAI1-PRJ-I (S3))
Program Officer
Quill, Helen R
Project Start
1999-09-30
Project End
2003-08-30
Budget Start
1999-09-30
Budget End
2000-08-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Trudeau Institute, Inc.
Department
Type
DUNS #
City
Saranac Lake
State
NY
Country
United States
Zip Code
12983
Tinoco, Roberto; Carrette, Florent; Henriquez, Monique L et al. (2018) Fucosyltransferase Induction during Influenza Virus Infection Is Required for the Generation of Functional Memory CD4+ T Cells. J Immunol 200:2690-2702
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
Marshall, Nikki B; Vong, Allen M; Devarajan, Priyadharshini et al. (2017) NKG2C/E Marks the Unique Cytotoxic CD4 T Cell Subset, ThCTL, Generated by Influenza Infection. J Immunol 198:1142-1155
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
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

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