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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


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:
Provided by: PubMed Central

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