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

Wooldridge, Linda, Lissina, Anna, Vernazza, Jonathan, Gostick, Emma, Laugel, Bruno Frederic, Hutchinson, Sarah L., Mirza, Fareed, Dunbar, P. Rod, Boulter, Jonathan M., Glick, Meir, Cerundolo, Vincenzo, Berg, Hugo A. van den, Price, David ORCID: https://orcid.org/0000-0001-9416-2737 and Sewell, Andrew ORCID: https://orcid.org/0000-0003-3194-3135 2007. Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region. European Journal of Immunology 37 (5) , pp. 1323-1333. 10.1002/eji.200636765

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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 ?2 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 ? 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Uncontrolled Keywords:	CD8 ; Cytotoxic T cells ; MHC class?I ; T cell activation ; Tumor immunity
ISSN:	15214141
Last Modified:	06 May 2023 02:22
URI:	https://orca.cardiff.ac.uk/id/eprint/342

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