Our primary defense against infectious disease and re-occurring illness are memory T and B cells. These critical arms of the immune system can also be potent aggressors against many forms of cancer. Developing effective vaccines to prevent infection and to treat chronic infection or cancer remains a formidable challenge primarily because we do not fully understand how memory T and B cells develop during immune responses. Recent work has significantly improved our knowledge of memory CDS T cell development during infection by outlining a complex differentiation process that occurs as CDS T cells transit through the different developmental stages (naive-> effector-> memory cell stages) of an immune response. More importantly, these studies gave rise to the identification of the cellular progenitors of memory CDS T cells. This investigator found a signature marker, the interleukin-7 receptor alpha-chain (IL-7Ralpha), that distinguished the subset of effector cells that would survive and develop into memory CDS T cells from those that would die. Thus, it is now possible to detect, isolate and manipulate the cells that will develop into protective memory CDS T cells, and this will greatly facilitate discovery of the mechanisms involved in memory T cell generation. This proposal aims to characterize the factors that regulate memory cell precursor development during viral and bacterial infection.
Aim 1 will investigate how key features of infection, such as inflammatory cytokines and the duration of antigenic stimulation, and IL-7 controls formation of memory CDS T cell precursors.
Aim 2 will examine 'where' memory CDS T cell progenitors form and test if secondary lymphoid organs are required.
This Aim will also investigate how lymphoid organs are involved in generating different types of memory CDS T cells, such as central and effector memory T cells that provide different levels of protective immunity.
Aim 3 will test if IL-7R signals can single-handedly drive the development of protective memory CDS T cells during acute infection and vaccination. IL-7R signaling is necessary for memory CDS T cell development, and this Aim will determine if it is sufficient or if additional signals are needed. At the conclusion of these studies, we will have a clearer understanding of the signals and mechanisms that control formation of memory CDS T cells during viral and bacterial infection, and this will greatly impact new generation vaccines and immunotherapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI066232-04
Application #
7342103
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Lapham, Cheryl K
Project Start
2005-05-01
Project End
2013-10-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$380,205
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Guan, Tianxia; Dominguez, Claudia X; Amezquita, Robert A et al. (2018) ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates. J Exp Med 215:1153-1168
Roberts, Natalie A; Adams, Brian D; McCarthy, Nicholas I et al. (2017) Prdm1 Regulates Thymic Epithelial Function To Prevent Autoimmunity. J Immunol 199:1250-1260
Buck, Michael D; Sowell, Ryan T; Kaech, Susan M et al. (2017) Metabolic Instruction of Immunity. Cell 169:570-586
Xin, Annie; Masson, Frederick; Liao, Yang et al. (2016) A molecular threshold for effector CD8(+) T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat Immunol 17:422-32
Laidlaw, Brian J; Craft, Joseph E; Kaech, Susan M (2016) The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev Immunol 16:102-11
Ray, John P; Staron, Matthew M; Shyer, Justin A et al. (2015) The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. Immunity 43:690-702
Chen, Jonathan H; Perry, Curtis J; Tsui, Yao-Chen et al. (2015) Prostaglandin E2 and programmed cell death 1 signaling coordinately impair CTL function and survival during chronic viral infection. Nat Med 21:327-34
Cui, Guoliang; Staron, Matthew M; Gray, Simon M et al. (2015) IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity. Cell 161:750-61
Dominguez, Claudia X; Amezquita, Robert A; Guan, Tianxia et al. (2015) The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. J Exp Med 212:2041-56
Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A et al. (2015) Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 16:871-9

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