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Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

By Linda Wooldridge, Anna Lissina, Jonathan Vernazza, Emma Gostick, Bruno Laugel, Sarah L Hutchinson, Fareed Mirza, P Rod Dunbar, Jonathan M Boulter, Meir Glick, Vincenzo Cerundolo, Hugo A van den Berg, David A Price and Andrew K Sewell

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 α2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by ∼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 ζ 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

Topics: Immunomodulation
Publisher: WILEY-VCH Verlag
OAI identifier: oai:pubmedcentral.nih.gov:2699427
Provided by: PubMed Central

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Citations

  1. (2007). 37: 1323–1333 1332 f
  2. (2001). A novel approach to antigen-specific deletion of CTL with minimal cellular activation using alpha3 domain mutants of MHC class I/peptide complex. Immunity
  3. (1996). A TCR binds to antagonist ligands with lower affinities and faster dissociation rates than to agonists. Immunity
  4. (2005). A.etal.,Interaction betweentheCD8coreceptor and major histocompatibility complex class I stabilizes T cell receptorantigen complexes at the cell surface.
  5. (2005). after redirection of their specificity by a high-affinity p53A2.1-specific TCR. Immunity
  6. and CD8: Modulators of T-cell receptor recognition of antigen and of immune responses?
  7. (1998). and lowpotency ligands with similar affinities for the TCR: The importance of kinetics in TCR signaling. Immunity
  8. (1997). Antagonism of cytotoxic T lymphocyte-mediated lysis by natural HIV-1 altered peptide ligands requires simultaneous presentation of agonist and antagonist peptides.
  9. (2003). Anti-CD8 antibodies can inhibit or enhance peptide-MHC class I (pMHCI) multimer binding: This is paralleled by their effectsonCTLactivationandoccursinthe absence ofaninteractionbetween pMHCI and CD8 on the cell surface.
  10. (1998). Antigen-specific release of beta-chemokines by anti-HIV-1 cytotoxic T lymphocytes.
  11. augments the response of a T cell to agonist but not to antagonist ligands. Immunity
  12. Avidity for antigen shapes clonal dominance in CD8 + Tcell populations specificfor persistent DNAviruses.
  13. (1997). B.,Comparison of the roles of CD8 alphaalpha and CD8 alpha beta in interaction with MHC class
  14. (2003). CD3 delta establishes a functional link between the T cell receptor and CD8.
  15. (2001). CD8beta endows CD8 with efficient coreceptor function by coupling T cell receptor/CD3 to raft-associated CD8/p56(lck) complexes.
  16. (2000). Classical and nonclassical class I major histocompatibility complex molecules exhibit subtle conformational differences that affect binding to CD8alphaalpha.
  17. (1998). Copresentation of natural HIV-1 agonist and antagonist ligands fails to induce the T cell receptor signaling cascade.
  18. (1997). Crystal structure of the complex between human CD8alpha(alpha) and HLA-A2. Nature
  19. (1998). Fidelity of T cell activation through multistep T cell receptor zeta phosphorylation. Science
  20. Functional and biophysical characterization of anHLA-A*6801-restrictedHIV-specificTcellreceptor.Eur.J.Immunol.2007.
  21. (2002). Inhibition of T cell receptorcoreceptor interactions by antagonist ligands visualized by live FRET imaging of the T-hybridoma immunological synapse. Immunity
  22. (1998). Initiation of signal transduction through the T cell receptor requires the multivalent engagement of peptide/MHC ligands. Immunity
  23. (2002). Interactions between MHC molecules and co-receptors of the TCR.
  24. (1999). Isolation of high avidity melanoma-reactive CTL from heterogeneous populations using peptide-MHC tetramers.
  25. kinetically promotes ligand binding to the T-cell antigen receptor.
  26. (1998). Ligand recognition by alpha beta T cell receptors.
  27. (1997). Low affinity interaction of human or rat Tcell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity.
  28. (2001). Mature dendritic cells prime functionally superior melan-A-specificCD8 +lymphocytesascomparedwithnonprofessionalAPC.
  29. modulation of T-cell antigen receptor-ligand interactions on living cytotoxic T lymphocytes. Nature
  30. (2002). Molecular coordination of alphabetaT-cell receptors and coreceptors CD8 and CD4 in their recognition of peptide-MHC ligands. Trends Immunol.
  31. (2003). Molecular interactions mediating T cell antigen recognition.
  32. (2002). Mouse MHC class I tetramers that are unable tobind toCD8revealtheneed forCD8 engagementinorder toactivatenaive CD8 T cells.
  33. (1999). Orientation of the Ig domains of CD8 alpha beta relative to MHC class
  34. (1996). Phenotypic analysis of antigen-specific T lymphocytes. Science
  35. (2003). Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity
  36. (1989). Species-restricted interactions between CD8 and the alpha 3 domain of class I influence the magnitude of the xenogeneic response.
  37. Substitutionatresidue 227ofH-2class Imoleculesabrogatesrecognitionby CD8-dependent, but not CD8-independent, cytotoxic T lymphocytes.
  38. (2001). T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule,
  39. (2004). Tcell killing does not require the formation of a stable mature immunological synapse.
  40. (1988). The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell
  41. (2003). The CD8 T cell coreceptor exhibits disproportionate biological activity at extremely low binding affinities.
  42. (1997). The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide-MHC molecule ligands.
  43. The human CD8 coreceptor effects cytotoxic T cell activation and antigen sensitivity primarily by mediating complete phosphorylation of the T cell receptor zeta chain.
  44. (2002). Thymic selection generates a large T cell pool recognizing a self-peptide in humans.
  45. (2002). Tracking T cells with tetramers: New tales from new tools.

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