title: Role of LAT in the granule-mediated cytotoxicity of CD8 T cells.
abstract: Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is essential to bridge T cell receptor (TCR) engagement to downstream signaling events. The indispensable role of LAT in thymocyte development and T cell activation has been well characterized; however, the function of LAT in cytotoxic-T-lymphocyte (CTL) cytotoxicity remains unknown. We show here that LAT-deficient CTLs failed to upregulate FasL and produce gamma interferon after engagement with target cells and had impaired granule-mediated killing. We further dissected the effect of the LAT deletion on each step of granule exocytosis. LAT deficiency led to altered synapse formation, subsequently causing unstable T cell-antigen-presenting cell (APC) conjugates. Microtubule organizing center polarization and granule reorientation were also impaired by LAT deficiency, leading to reduced granule delivery. Despite these defects, granule release was still observed in LAT-deficient CTLs due to residual calcium flux and phospholipase C (PLC) activity. Our data demonstrated that LAT-mediated signaling intricately regulates CTL cytotoxicity at multiple steps.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Chih-wen
authors.initials: CW
authors.lastname: Ou-Yang
authors.forename: Minghua
authors.initials: M
authors.lastname: Zhu
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: Fuller
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sullivan
authors.forename: Mariana I
authors.initials: MI
authors.lastname: Chuck
authors.forename: Sarah
authors.initials: S
authors.lastname: Ogden
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D020013:Calcium Signaling / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005089:Exocytosis / Q000276:immunology; D053222:Fas Ligand Protein / Q000378:metabolism; D054992:Immunological Synapses / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D022142:Secretory Vesicles / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma