title: Enhanced T-cell activation and differentiation in lymphocytes from transgenic mice expressing ubiquitination-resistant 2KR LAT molecules.
abstract: Linker for activation of T cells (LAT) is critical for the propagation of T-cell signals upon T-cell receptor (TCR) activation. Previous studies demonstrated that substitution of LAT lysines with arginines (2KR LAT) resulted in decreased LAT ubiquitination and elevated T-cell signaling, indicating that LAT ubiquitination is a molecular checkpoint for attenuation of T-cell signaling. To investigate the role of LAT ubiquitination in vivo, we have generated transgenic mice expressing WT and ubiquitin-defective 2KR LAT. On TCR stimulation of T cells from these mice, proximal signaling and cytokine production was elevated in 2KR versus wild-type (WT) LAT mice. Enhanced cytolytic activity as well as T-helper responses were observed on LAT expression, which were further elevated by 2KR LAT expression. Despite greater T-effector function, WT or 2KR LAT expression did not have any effect on clearance of certain pathogens or tumors. Our data support the model that lack of tumor clearance is due to increased differentiation and acquisition of effector phenotype that is associated with suboptimal immunity in an immunotherapy model. Thus, our data further reinforce the role of LAT ubiquitination in TCR signaling and uncovers a novel role for LAT in driving T-cell differentiation.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Centro de Investigación del Cáncer, Salamanca, Spain.|Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, Salamanca, Spain.
authors.forename: A B
authors.initials: AB
authors.lastname: Rodriguez-Peña
authors.affiliation: Cell Signaling and Immunity Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gomez-Rodriguez
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Department of Pharmacology; Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Kortum
authors.affiliation: Tumor Immunology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Palmer
authors.affiliation: Tumor Immunology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: G C
authors.initials: GC
authors.lastname: Guittard
authors.affiliation: Immunity at Barrier Sites Initiative, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.|Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.|Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, NY, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Wohlfert
authors.affiliation: Immunoregulation Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Silver
authors.affiliation: Center for Biologics Evaluation & Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Misplon
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Sommers
authors.affiliation: Laboratory Animal Sciences Program, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Feigenbaum
authors.affiliation: Center for Biologics Evaluation & Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Epstein
authors.affiliation: Immunoregulation Section, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Caspi
authors.affiliation: Immunity at Barrier Sites Initiative, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.|Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Belkaid
authors.affiliation: Tumor Immunology Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: N P
authors.initials: NP
authors.lastname: Restifo
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Samelson
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Balagopalan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000276:immunology; D019943:Amino Acid Substitution; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000235:genetics* / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell