T lymphocytes are critical to adaptive immunity. Controlled motility and arrest permit them to rapidly survey tissues and to focus their effector functions on target cells and organs when required. When engaged by antigen-presenting cells, T cells organize their membranes to create signaling structures that facilitate effector function and influence differentiation into effector cells. Despite a profoundly renewed appreciation of the role of cell motility, arrest and cellular polarization in influencing T cell activation in vivo, there are few studies that address the specifics of how motility and arrest are controlled in T cells. Studies over the last decade have clearly implicated myosin motors in motility, membrane protein distribution and many other cellular functions. However, we know very little about myosin function in T cells. We have identified a primary modulator of T cell velocity and crawling mode- the only Myosin II isoform expressed in T cells - and have demonstrated the putative pathway whereby TCR and (likely) accessory signals modulate its function for motility and arrest. We hypothesize that T cell amoeboid motility is modulated via phosphorylation level and overall amount of Myosin IIA (MyoIIA) heavy chains. MyoIIA regulation is likely to facilitate changes in motility mode, including arrest and `licensing'of synapse establishment. In the course of testing this hypothesis, we will also test whether a human MyoIIA disorder caused by a natural mutation in the assembly competence (phosphorylation) domain may also contribute to an immune dysfunction in these patients. Complementary studies in other cell types and in lower organisms have also led us to propose that Myosin I isoforms regulate cell motility and synapse dynamics. We hypothesize that MyoIc serves complementary functions to MyoIIA by organizing the membrane and associated proteins predominantly at the leading edge and arranging membrane microclusters at the synapse. The underlying model is that MyoIIA squeezes actin-based structures from behind to influence where cellular extension is promoted whereas Myosin I travels on existing actin to carry critical cellular components into those new areas to influence the biochemistry there. Our goal is to determine how TCR triggering during the first contact may lead to the effective mobilization of these motors and how this subsequently results in the manufacture of a well-behaved surface contact, including microcluster and signalosome assemblies. Motility and the control of cellular protein distributions are all critical to the T cell response. The benefits of modulating these processes may include augmentation of T cell responses, for example against pathogens and tumors as well as characterization and treatment of genetic disorders of Myosin II. Project Narrative: T cells are the primary sentinels of the immune system and they constantly move around to seek out invading organisms and initiate responses against these. Here, we seek to understand how these cells control their movements, and how the mechanisms that make them move are changed when they sense dangers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052116-09
Application #
8004086
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2002-09-15
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
9
Fiscal Year
2011
Total Cost
$372,830
Indirect Cost
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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; 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
Mujal, Adriana M; Krummel, Matthew (2015) The subtle hands of self-reactivity in peripheral T cells. Nat Immunol 16:10-1
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
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
Gérard, 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
Pinkard, Henry; Stuurman, Nico; Corbin, Kaitlin et al. (2013) Micro-Magellan: open-source, sample-adaptive, acquisition software for optical microscopy. Nat Methods 13:807-809

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