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)
Project #
Application #
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Krummel, Matthew F; Mahale, Jagdish N; Uhl, Lion F K et al. (2018) Paracrine costimulation of IFN-? signaling by integrins modulates CD8 T cell differentiation. Proc Natl Acad Sci U S A 115:11585-11590
Cai, En; Marchuk, Kyle; Beemiller, Peter et al. (2017) Visualizing dynamic microvillar search and stabilization during ligand detection by T cells. Science 356:
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
Pinkard, Henry; Stuurman, Nico; Corbin, Kaitlin et al. (2016) Micro-Magellan: open-source, sample-adaptive, acquisition software for optical microscopy. Nat Methods 13:807-809
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

Showing the most recent 10 out of 34 publications