title: Targeted suppression of autoreactive CD8+T-cell activation using blocking anti-CD8 antibodies.
abstract: CD8+T-cells play a role in the pathogenesis of autoimmune diseases such as multiple sclerosis and type 1 diabetes. However, drugs that target the entire CD8+T-cell population are not desirable because the associated lack of specificity can lead to unwanted consequences, most notably an enhanced susceptibility to infection. Here, we show that autoreactive CD8+T-cells are highly dependent on CD8 for ligand-induced activation via the T-cell receptor (TCR). In contrast, pathogen-specific CD8+T-cells are relatively CD8-independent. These generic differences relate to an intrinsic dichotomy that segregates self-derived and exogenous antigen-specific TCRs according to the monomeric interaction affinity with cognate peptide-major histocompatibility complex class I (pMHCI). As a consequence, "blocking" anti-CD8 antibodies can suppress autoreactive CD8+T-cell activation in a relatively selective manner. These findings provide a rational basis for the development and in vivo assessment of novel therapeutic strategies that preferentially target disease-relevant autoimmune responses within the CD8+T-cell compartment.
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Pearson
authors.affiliation: Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.|Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gras
authors.affiliation: Mathematics Institute, University of Warwick, Coventry CV4 7AL, UK.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: van den Berg
authors.affiliation: Faculty of Health Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Anya
authors.initials: A
authors.lastname: Lissina
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Sian
authors.initials: S
authors.lastname: Llewellyn-Lacey
authors.affiliation: Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Willis
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Tamsin
authors.initials: T
authors.lastname: Dockree
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: James E
authors.initials: JE
authors.lastname: McLaren
authors.affiliation: Mucosal Infection and Immunity Group, Department of Medicine, Imperial College London, London SW7 2AZ, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Ekeruche-Makinde
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.affiliation: Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Robertson
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.|Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.|Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD 4029, Australia.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.|Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: Division of Infection and Immunity, Cardiff University, Cardiff CF14 4XN, UK.
authors.forename: F Susan
authors.initials: FS
authors.lastname: Wong
authors.affiliation: Department of Immunobiology, King's College London, London SE1 9RT, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.affiliation: Department of Immunobiology, King's College London, London SE1 9RT, UK.
authors.forename: Ania
authors.initials: A
authors.lastname: Skowera
authors.affiliation: Faculty of Health Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002460:Cell Line; D000939:Epitopes / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007165:Immunosuppression Therapy; D007515:Islets of Langerhans / Q000378:metabolism; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010455:Peptides / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
chemical_list: D000906:Antibodies; D016827:CD8 Antigens; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D011948:Receptors, Antigen, T-Cell