title: Kinetics of early T cell receptor signaling regulate the pathway of lytic granule delivery to the secretory domain.
abstract: Cytolytic granules mediate killing of virus-infected cells by cytotoxic T lymphocytes. We show here that the granules can take long or short paths to the secretory domain. Both paths utilized the same intracellular molecular events, which have different spatial and temporal arrangements and are regulated by the kinetics of Ca(2+)-mediated signaling. Rapid signaling caused swift granule concentration near the microtubule-organizing center (MTOC) and subsequent delivery by the polarized MTOC directly to the secretory domain-the shortest path. Indolent signaling led to late recruitment of granules that moved along microtubules to the periphery of the synapse and then moved tangentially to fuse at the outer edge of the secretory domain-a longer path. The short pathway is associated with faster granule release and more efficient killing than the long pathway. Thus, the kinetics of early signaling regulates the quality of the T cell cytolytic response.
authors.affiliation: Department of Microbiology and Immunology and Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Beal
authors.forename: Nadia
authors.initials: N
authors.lastname: Anikeeva
authors.forename: Rajat
authors.initials: R
authors.lastname: Varma
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Cameron
authors.forename: Gaia
authors.initials: G
authors.lastname: Vasiliver-Shamis
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Norris
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sykulev
mesh_terms: D001692:Biological Transport / Q000187:drug effects / Q000276:immunology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D054992:Immunological Synapses / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D022101:Microtubule-Organizing Center / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D007476:Ionophores; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D002118:Calcium