T cells utilize surface-bound T cell receptors (TCR) at the immunological synapse with antigen-presenting cells (APC). Detection of their peptide-MHC ligands results in rapid intracellular signaling, necessary for acquisition of effector functions and for profound adaptive immunity. While we now understand some of the fundamental proteins in this processing, understanding how each works together in the context of a rapidly moving T cell has proven difficult. TCR recognition happens as surface deformations provide initial contact. However, despite various fixed and lower-resolution approaches to understanding this process, it has not been previously possible to study this complete surface in real-time in the full 3-dimensions in which it takes place. Here, we will use novel and advanced imaging approaches to define how cytoskeletally-driven membrane movements provide a backbone for efficient ligand detection and we will describe how a range of widely variant environmental cues as well as novel pathways alter this process and affect immune surveillance. This project will define how T cells effectively `find' their ligands amidst a sea of competing MHC. This efficiency of search and detection has clear implications for the ability of T cells to discovery rare epitopes and initiate a response, for example during the early phases of a viral infection.
T cells must scan their environment, remaining optimizing sensitivity and speed. This study will understand how immune cells are able to be both sensitive and efficient in surveying their environment. It will also help explain how ligands are sensed, through the stabilization of microvillar-projections.
| 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 |
| 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 |
| 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 |
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