Program Director/Principal Investigator (Robey, Ellen, A): Summary: T cells orchestrate immune responses, and defects in T cell development in the thymus can lead to auto- immunity or immunodeficiency. We have developed new methods to directly visualize and manipulate the pattern of TCR signaling during T cell development in living thymic tissue. By examining the impact of these manipulations on T cell development, we expect to gain insights into the mechanistic connections between TCR signaling, thymocyte migration, and different forms of T cell selection. Such information is key to developing improved treatments for a variety of immune system related diseases and to improving our ability to manipulate immune response to tumors or pathogens. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) 2 Page Continuation Format Page

Public Health Relevance

Robey, Ellen, A): Narrative: T cells are blood cells that arise in the thymus and that orchestrate immune responses to pathogens or tumors. We are using advanced microscopy methods to directly visualize the process of T cell development in the thymus, with the ultimate goal of developing improved T cell-based therapies. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) 1 Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI064227-12
Application #
9233965
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Prabhudas, Mercy R
Project Start
2005-03-01
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
12
Fiscal Year
2017
Total Cost
$383,032
Indirect Cost
$133,032
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Ross, Jenny O; Melichar, Heather J; Halkias, Joanna et al. (2016) Studying T Cell Development in Thymic Slices. Methods Mol Biol 1323:131-40
Kurd, Nadia; Robey, Ellen A (2016) T-cell selection in the thymus: a spatial and temporal perspective. Immunol Rev 271:114-26
Weist, Brian M; Kurd, Nadia; Boussier, Jeremy et al. (2015) Thymic regulatory T cell niche size is dictated by limiting IL-2 from antigen-bearing dendritic cells and feedback competition. Nat Immunol 16:635-41
Melichar, Heather J; Ross, Jenny O; Taylor, Kayleigh T et al. (2015) Stable interactions and sustained TCR signaling characterize thymocyte-thymocyte interactions that support negative selection. J Immunol 194:1057-1061
Halkias, Joanna; Yen, Bonnie; Taylor, Kayleigh T et al. (2015) Conserved and divergent aspects of human T-cell development and migration in humanized mice. Immunol Cell Biol 93:716-26
Au-Yeung, Byron B; Melichar, Heather J; Ross, Jenny O et al. (2014) Quantitative and temporal requirements revealed for Zap70 catalytic activity during T cell development. Nat Immunol 15:687-94
Ross, Jenny O; Melichar, Heather J; Au-Yeung, Byron B et al. (2014) Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns. Proc Natl Acad Sci U S A 111:E2550-8
Dzhagalov, Ivan Lilyanov; Chen, Katherine Grace; Herzmark, Paul et al. (2013) Elimination of self-reactive T cells in the thymus: a timeline for negative selection. PLoS Biol 11:e1001566
Melichar, Heather J; Ross, Jenny O; Herzmark, Paul et al. (2013) Distinct temporal patterns of T cell receptor signaling during positive versus negative selection in situ. Sci Signal 6:ra92
Halkias, Joanna; Melichar, Heather J; Taylor, Kayleigh T et al. (2013) Opposing chemokine gradients control human thymocyte migration in situ. J Clin Invest 123:2131-42

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