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

L Wooldridge, A Lissina, J Vernazza… - European journal of …, 2007 - Wiley Online Library
L Wooldridge, A Lissina, J Vernazza, E Gostick, B Laugel, SL Hutchinson, F Mirza
European journal of immunology, 2007Wiley Online Library
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 …
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.
Wiley Online Library