The peripheral T cell pool in healthy individuals is maintained by both thymic output and peripheral homeostasis. The thymus exports newly generated T cells throughout the lifetime of the individual. These cells, called recent thymic emigrants or RTEs, predominate in the neonatal period and in the adult, are crucial for maintaining T cell diversity and in reconstituting the naive T cell pool following lymphodepletion through infection or therapeutic intervention. Using a mouse model system in which RTEs can be distinguished from the bulk of peripheral T cells, it is now clear that T cells continue to mature for 2-3 weeks after thymic egress. Activated CD4 and CD8 RTEs exhibit diminished proliferation, decreased cytokine production, and altered surface antigen phenotype compared to similarly treated mature T cells. This distinct functional profile lasts well after RTEs have entered the mature peripheral T cell pool. Proposed experiments encompass the following specific aims:
Specific Aim 1 : To determine whether CD4 RTEs show a bias against the Th1 and toward theTh2 lineage in vivo. These experiments will determine whether RTEs mount deficient Th1 responses and enhanced Th2 responses in vivo.
Specific Aim 2 : To investigate whether the epigenetic control of cytokine loci in RTEs is distinct from that in mature naive T cells. These experiments will assess the plasticity of lineage-committed CD4 RTEs and will investigate chromatin modifications at the Th2, Il2, and Ifng loci of naive and polarized CD4 RTEs and at the Il2 and Ifng loci of naive and activated CD8 RTEs, in an effort to understand the mechanism behind the heritable changes in cytokine expression that distinguish RTEs from mature T cells.
Specific Aim 3 : To analyze the comparative strength of TCR signal transduction in RTEs and mature naive T cells. These experiments will investigate the events downstream of the TCR leading to dampened RTE responses, the expression of transcription factors that regulate anergy induction and memory/effector cell fate decisions, and the impact of ligand affinity and antigen persistence on RTE function. The focus of these experiments is to understand the relationship between RTE functional traits and anergy and to probe the manner in which RTEs interpret environmental cues that is distinct from their mature counterparts. The overall goal of these studies is to understand the biology of RTEs, a key but under-studied population of peripheral T cells.

Public Health Relevance

The steady export of newly generated T cells (or recent thymic emigrants) is required to maintain the diversity of the T cell compartment throughout life. Recent thymic emigrants make up the bulk of the peripheral T cell pool in neonates, and are required to reconstitute the depleted naive T cell pool in adults. Thus, understanding the biology of recent thymic emigrants is crucial to predicting immune responses in neonates and in adults recovering from lymphodepleting viral infections or therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064318-08
Application #
8300173
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Prabhudas, Mercy R
Project Start
2010-07-15
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$412,560
Indirect Cost
$146,413
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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
Vanden Driessche, Koen; Persson, Alexander; Marais, Ben J et al. (2013) Immune vulnerability of infants to tuberculosis. Clin Dev Immunol 2013:781320
Fink, Pamela J (2013) The biology of recent thymic emigrants. Annu Rev Immunol 31:31-50
Berkley, Amy M; Hendricks, Deborah W; Simmons, Kalynn B et al. (2013) Recent thymic emigrants and mature naive T cells exhibit differential DNA methylation at key cytokine loci. J Immunol 190:6180-6
Houston Jr, Evan G; Boursalian, Tamar E; Fink, Pamela J (2012) Homeostatic signals do not drive post-thymic T cell maturation. Cell Immunol 274:39-45
Fink, Pamela J; Hendricks, Deborah W (2011) Post-thymic maturation: young T cells assert their individuality. Nat Rev Immunol 11:544-9
Hendricks, Deborah W; Fink, Pamela J (2011) Recent thymic emigrants are biased against the T-helper type 1 and toward the T-helper type 2 effector lineage. Blood 117:1239-49
Houston Jr, Evan G; Higdon, Lauren E; Fink, Pamela J (2011) Recent thymic emigrants are preferentially incorporated only into the depleted T-cell pool. Proc Natl Acad Sci U S A 108:5366-71
Do, Jeong-su; Fink, Pamela J; Li, Lily et al. (2010) Cutting edge: spontaneous development of IL-17-producing gamma delta T cells in the thymus occurs via a TGF-beta 1-dependent mechanism. J Immunol 184:1675-9
Hendricks, Deborah W; Fink, Pamela J (2009) Uneven colonization of the lymphoid periphery by T cells that undergo early TCR{alpha} rearrangements. J Immunol 182:4267-74

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