In the past few years, advances in imaging methods have made it possible to track cell movement within 3 dimensional tissues, opening up a new frontier in understanding the in vivo control of cell migration. The thymus of the mouse is an ideal experimental system to explore this problem, since developing T cells are highly motile and undergo long range migrations that are tightly linked to their developmental program. Our general approach consists of three phases. 1) We will use 2-photon imaging to observe and quantitate thymocyte migration deep within the thymus and to form initial hypotheses about how thymocyte motility is regulated. 2) We will refine our hypotheses using stochastic computer simulations to assess how factors such as attractive/repulsive molecules, adhesion proteins, inherent motility and cell packing could effect thymocyte migration. 3) We will then test our hypotheses by experimentally altering these factors and examining the effect of these alterations on thymocyte migration and TCR repertoire selection. This fundamental information about the process whereby immature thymic precursors give rise to mature, functional T cells, will improve our ability to manipulate the immune response to disease and to improve human health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Prabhudas, Mercy R
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University of California Berkeley
Schools of Arts and Sciences
United States
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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
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
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
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
Dzhagalov, Ivan L; Melichar, Heather J; Ross, Jenny O et al. (2012) Two-photon imaging of the immune system. Curr Protoc Cytom Chapter 12:Unit12.26

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