Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class[emsp13]I invariant region

نویسندگان

  • 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
  • Andrew K. Sewell
  • Peter Medawar
چکیده

CD8 cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptideMHC 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 a2 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 f 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.

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

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تاریخ انتشار 2007