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.
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.
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|Mujal, Adriana M; Gilden, Julia K; Gérard, Audrey et al. (2016) A septin requirement differentiates autonomous and contact-facilitated T cell proliferation. Nat Immunol 17:315-22|
|Krummel, Matthew F; Bartumeus, Frederic; Gérard, Audrey (2016) T cell migration, search strategies and mechanisms. Nat Rev Immunol 16:193-201|
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|Pinkard, Henry; Corbin, Kaitlin; Krummel, Matthew F (2016) Spatiotemporal Rank Filtering Improves Image Quality Compared to Frame Averaging in 2-Photon Laser Scanning Microscopy. PLoS One 11:e0150430|
|Mujal, Adriana M; Krummel, Matthew (2015) The subtle hands of self-reactivity in peripheral T cells. Nat Immunol 16:10-1|
|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|
|Corbin, Kaitlin; Pinkard, Henry; Peck, Sebastian et al. (2014) Assessing and benchmarking multiphoton microscopes for biologists. Methods Cell Biol 123:135-51|
|Gérard, 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|
|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|
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