title: Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region.
abstract: CD8(+) cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 zeta chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.
authors: Department of Medical Biochemistry & Immunology, University of Cardiff, Cardiff, UK. wooldridgeL@cardiff.ac.uk
authors: Linda
authors: L
authors: Wooldridge
authors: Anna
authors: A
authors: Lissina
authors: Jonathan
authors: J
authors: Vernazza
authors: Emma
authors: E
authors: Gostick
authors: Bruno
authors: B
authors: Laugel
authors: Sarah L
authors: SL
authors: Hutchinson
authors: Fareed
authors: F
authors: Mirza
authors: P Rod
authors: PR
authors: Dunbar
authors: Jonathan M
authors: JM
authors: Boulter
authors: Meir
authors: M
authors: Glick
authors: Vincenzo
authors: V
authors: Cerundolo
authors: Hugo A
authors: HA
authors: van den Berg
authors: David A
authors: DA
authors: Price
authors: Andrew K
authors: AK
authors: Sewell
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D016827:CD8 Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020349:Surface Plasmon Resonance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
chemical_list: D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell