title: MHC class I molecules with Superenhanced CD8 binding properties bypass the requirement for cognate TCR recognition and nonspecifically activate CTLs.
abstract: CD8(+) CTLs are essential for effective immune defense against intracellular microbes and neoplasia. CTLs recognize short peptide fragments presented in association with MHC class I (MHCI) molecules on the surface of infected or dysregulated cells. Ag recognition involves the binding of both TCR and CD8 coreceptor to a single ligand (peptide MHCI [pMHCI]). The TCR/pMHCI interaction confers Ag specificity, whereas the pMHCI/CD8 interaction mediates enhanced sensitivity to Ag. Striking biophysical differences exist between the TCR/pMHCI and pMHCI/CD8 interactions; indeed, the pMHCI/CD8 interaction can be >100-fold weaker than the cognate TCR/pMHCI interaction. In this study, we show that increasing the strength of the pMHCI/CD8 interaction by approximately 15-fold results in nonspecific, cognate Ag-independent pMHCI tetramer binding at the cell surface. Furthermore, pMHCI molecules with superenhanced affinity for CD8 activate CTLs in the absence of a specific TCR/pMHCI interaction to elicit a full range of effector functions, including cytokine/chemokine release, degranulation and proliferation. Thus, the low solution binding affinity of the pMHCI/CD8 interaction is essential for the maintenance of CTL Ag specificity.
authors.affiliation: Department of Infection, Cardiff University, Cardiff, United Kingdom. wooldridgel@cardiff.ac.uk
authors.forename: Linda
authors.initials: L
authors.lastname: Wooldridge
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.forename: Anna
authors.initials: A
authors.lastname: Lissina
authors.forename: Emily S J
authors.initials: ES
authors.lastname: Edwards
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Julia
authors.initials: J
authors.lastname: Ekeruche
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Hewitt
authors.forename: Bruno
authors.initials: B
authors.lastname: Laugel
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: David K
authors.initials: DK
authors.lastname: Cole
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.forename: Cor
authors.initials: C
authors.lastname: Berrevoets
authors.forename: John J
authors.initials: JJ
authors.lastname: Miles
authors.forename: Scott R
authors.initials: SR
authors.lastname: Burrows
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
mesh_terms: D017951:Antigen Presentation / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell