T lymphocytes require dynamic movement for all of their critical functions. Motility, synapse formation and signaling are intricately linked through he actions of the cellular cytoskeleton. Data from our lab and others indicates that the T cell cortex is tightly regulated from within, using myosin motors and the associated septin cytoskeleton that control cortical integrity and membrane tension, all of which function via intimate association with a continuously remodeling actin cytoskeleton. This control has profound implications for the process of scanning organs for antigens, for the process of interacting with antigen-presenting cells, and for the process of interacting with targets. It is clear that there remains a dearth of understanding about which individual system controls T cell membrane biology and specifically how these: 1. Control cell-intrinsic scanning behavior such that organs are completely surveyed. 2. Control cortical and membrane tension so that membrane-membrane interactions (synapses) are optimized. 3. Drive the large-scale aggregation of proteins into domains that encourage signaling or lead to its cessation. This project will study these fundamental issues. We have assembled an unrivalled panel of genetic knockouts in the myosin/septin pathway and have revealed critical roles actin depolymerization as a co-factor in synapses and likely cell motility. This project will delve into how the T cell works in its native habitat and will reveal nvel mechanisms that regulate immunity and tolerance.

Public Health Relevance

Many activities in the immune system are controlled as a result the movement and interactions of T cells within organs. To seek how to improve T cell functions, we are seeking to understand the basis by which these cells 'scan'our tissues and recognize infections or respond to vaccines. Specifically, we will determine the role of three families of proteins that variously apply tension to the membrane and affect the dynamics of cell membranes as they engage with the tissues to be scanned.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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GĂ©rard, Audrey; Patino-Lopez, Genaro; Beemiller, Peter et al. (2014) Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g. Cell 158:492-505
Krummel, Matthew F; Friedman, Rachel S; Jacobelli, Jordan (2014) Modes and mechanisms of T cell motility: roles for confinement and Myosin-IIA. Curr Opin Cell Biol 30:9-16
Jacobelli, Jordan; Estin Matthews, Miriam; Chen, Stephanie et al. (2013) Activated T cell trans-endothelial migration relies on myosin-IIA contractility for squeezing the cell nucleus through endothelial cell barriers. PLoS One 8:e75151
Gerard, Audrey; Beemiller, Peter; Friedman, Rachel S et al. (2013) Evolving immune circuits are generated by flexible, motile, and sequential immunological synapses. Immunol Rev 251:80-96
Gerard, Audrey; Khan, Omar; Beemiller, Peter et al. (2013) Secondary T cell-T cell synaptic interactions drive the differentiation of protective CD8+ T cells. Nat Immunol 14:356-63
Beemiller, Peter; Krummel, Matthew F (2013) Regulation of T-cell receptor signaling by the actin cytoskeleton and poroelastic cytoplasm. Immunol Rev 256:148-59
Gilden, Julia K; Peck, Sebastian; Chen, Yi-Chun M et al. (2012) The septin cytoskeleton facilitates membrane retraction during motility and blebbing. J Cell Biol 196:103-14
Jacobelli, Jordan; Bennett, F Chris; Pandurangi, Priya et al. (2009) Myosin-IIA and ICAM-1 regulate the interchange between two distinct modes of T cell migration. J Immunol 182:2041-50
Tooley, Aaron J; Gilden, Julia; Jacobelli, Jordan et al. (2009) Amoeboid T lymphocytes require the septin cytoskeleton for cortical integrity and persistent motility. Nat Cell Biol 11:17-26
Mamchak, Alusha A; Sullivan, Brandon M; Hou, Baidong et al. (2008) Normal development and activation but altered cytokine production of Fyn-deficient CD4+ T cells. J Immunol 181:5374-85

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