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 #
5R01AI052116-10
Application #
8206581
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
2012-01-01
Budget End
2012-12-31
Support Year
10
Fiscal Year
2012
Total Cost
$372,659
Indirect Cost
$127,634
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
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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