The thymus plays amajor role in the establishment andmaintenance oftheperipheral I cell pool throughout the lifespan of the animal. In work from this laboratory, recent thymic emigrants (RTEs) have been marked in mice transgenic for green fluorescent protein (GFP) under the control of the RAG2 promoter. GFP expression initiates at the expected developmental stage, but the GFP signal lingers after RAG2 expression is extinguished. The resulting GFP peripheral T cells are RTEs, disappearing within one week of thymectomy. Recent data show that GFPhl peripheral T cells undergo phenotypic and functional maturation in the lymphoid periphery. Within the RTE population, the CD4:CD8 ratio is higher, CD24 expression is higher, and Qa-2 expression is lower than on more mature peripheral T cells. CD8+ RTEs contain half the expected cytolytic precursors, and without exogenous IL-2, CD4+ RTEs proliferate poorly upon TCR crosslinking. One focus of the present investigation is to explore whether the continued maturation of RTEs in the lymphoid periphery is a selective process, requiring chemokine/receptor or TCR/ligand interactions. These experiments determine whether MHC molecules and IL-7 are required for the continued maturation and survival of CD4+ and CD8* RTEs in the lymphoid periphery. Furthermore, the TCR repertoire of RTEs will be analyzed and compared with that of their mature peripheral counterparts, and it will be determined whether RTEs compete with each other for maturation signals on the basis of TCR specificity. An additional focus will be to define the basis for the functional defects that characterize RTEs and the impact of these defects on the induction of T cell tolerance and the generation of long-term T cell memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI064318-04S1
Application #
7584702
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Lapham, Cheryl K
Project Start
2008-04-15
Project End
2010-03-31
Budget Start
2008-04-15
Budget End
2009-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$59,757
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Cunningham, Cody A; Hoppins, Suzanne; Fink, Pamela J (2018) Cutting Edge: Glycolytic Metabolism and Mitochondrial Metabolism Are Uncoupled in Antigen-Activated CD8+ Recent Thymic Emigrants. J Immunol 201:1627-1632
Cunningham, Cody A; Helm, Eric Y; Fink, Pamela J (2018) Reinterpreting recent thymic emigrant function: defective or adaptive? Curr Opin Immunol 51:1-6
Cunningham, Cody A; Bergsbaken, Tessa; Fink, Pamela J (2017) Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8+ Recent Thymic Emigrants. J Immunol 198:4575-4580
Bergsbaken, Tessa; Bevan, Michael J; Fink, Pamela J (2017) Local Inflammatory Cues Regulate Differentiation and Persistence of CD8+ Tissue-Resident Memory T Cells. Cell Rep 19:114-124
Friesen, Travis J; Ji, Qingyong; Fink, Pamela J (2016) Recent thymic emigrants are tolerized in the absence of inflammation. J Exp Med 213:913-20
Deets, Katherine A; Berkley, Amy M; Bergsbaken, Tessa et al. (2016) Cutting Edge: Enhanced Clonal Burst Size Corrects an Otherwise Defective Memory Response by CD8+ Recent Thymic Emigrants. J Immunol 196:2450-5
Moguche, Albanus O; Shafiani, Shahin; Clemons, Corey et al. (2015) ICOS and Bcl6-dependent pathways maintain a CD4 T cell population with memory-like properties during tuberculosis. J Exp Med 212:715-28
Philip, Mary; Funkhouser, Scott A; Chiu, Edison Y et al. (2015) Heme exporter FLVCR is required for T cell development and peripheral survival. J Immunol 194:1677-85
Berkley, Amy M; Fink, Pamela J (2014) Cutting edge: CD8+ recent thymic emigrants exhibit increased responses to low-affinity ligands and improved access to peripheral sites of inflammation. J Immunol 193:3262-6
Fink, Pamela J (2013) The biology of recent thymic emigrants. Annu Rev Immunol 31:31-50

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