Antigenically naive CD4 expressing a?-T cell receptors are critical for generating immune responses to neoantigens, and are produced de novo within the thymus as mature CD4+CD8- thymocytes. These enter the periphery to become recent thymic emigrants (RTEs) of the naive CD4 T-cell compartment. Although monitoring of CD4 RTEs is of great clinical interest, particularly in CD4 T-cell lymphopenia, direct evaluation of human CD4 RTEs has been limited by a lack of specific surface markers. This project will utilize a novel and recently identified surface marker for human CD4 RTEs, protein tyrosine kinase 7 (PTK7), to define CD4 RTE frequency, phenotype, and function. Preliminary results validate PTK7 as a CD4 RTE marker, and show that PTK7+ CD4 RTEs have a reduced capacity for effector function compared to PTK7- naive CD4 T cells.
Aim 1 will use gene expression profiling by deep mRNA sequencing of unstimulated and stimulated PTK7+ CD4 RTEs and other CD4 T-lineage cells to: 1) define the extent of residual thymocyte gene expression in PTK7+ CD4 RTEs during ontogeny, and 2) identify gene products involved in reduced CD4 RTE immune function, particularly for Th1 generation and/or that subdivide PTK7+ CD4 RTEs into more versus less recent thymic emigrants.
Aim 2 will use in vivo labeling to test the hypothesis that PTK7+ CD4 RTEs are the direct precursors of PTK7- naive CD4 T cells, and will determine the role of PTK7+ CD4 RTEs in maintaining naive CD4 T-cell numbers and 12-TCR repertoire diversity in HIV-1 infection.
Aim 3 will use a similar approach to test the importance of PTK7+ CD4 RTEs in immune reconstitution of naive CD4 T cells after allogeneic hematopoietic stem cell transplantation.
Aim 4 will define the kinetics of loss of PTK7+ CD4 RTEs in children and adults following complete thymectomy and the impact of this loss on naive CD4 T-cell numbers and 12- TCR repertoire diversity. Together, these studies will substantially enhance our understanding of the role of thymic RTE production in maintaining the peripheral naive CD4 T-cell compartment in health and disease.

Public Health Relevance

The production of new CD4 T cells by the thymus, which are also known as CD4 recent thymic emigrants (RTEs), is important for the immune system to respond to infections and vaccines. This research will evaluate the production and function of CD4 RTEs, in healthy individuals and in patients with diseases or treatments that may alter RTE production;this knowledge will also help identify patients that might benefit by treatment with drugs to increase RTE production.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083757-03
Application #
8212566
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Prabhudas, Mercy R
Project Start
2010-02-15
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
3
Fiscal Year
2012
Total Cost
$403,367
Indirect Cost
$123,655
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Holmes, Tyson H; Lewis, David B (2014) Bayesian immunological model development from the literature: example investigation of recent thymic emigrants. J Immunol Methods 414:32-50
Palin, Amy C; Ramachandran, Vasavi; Acharya, Swati et al. (2013) Human neonatal naive CD4+ T cells have enhanced activation-dependent signaling regulated by the microRNA miR-181a. J Immunol 190:2682-91
Bhaumik, Suniti; Giffon, Thierry; Bolinger, Derek et al. (2013) Retinoic acid hypersensitivity promotes peripheral tolerance in recent thymic emigrants. J Immunol 190:2603-13
Lewis, D B; Haines, C; Ross, D (2011) Protein tyrosine kinase 7: a novel surface marker for human recent thymic emigrants with potential clinical utility. J Perinatol 31 Suppl 1:S72-81