Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region.
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 alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 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 zeta 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.
Wooldridge
Linda
L
Department of Medical Biochemistry & Immunology, University of Cardiff, Cardiff, UK. wooldridgeL@cardiff.ac.uk
Lissina
Anna
A
Vernazza
Jonathan
J
Gostick
Emma
E
Laugel
Bruno
B
Hutchinson
Sarah L
SL
Mirza
Fareed
F
Dunbar
P Rod
PR
Boulter
Jonathan M
JM
Glick
Meir
M
Cerundolo
Vincenzo
V
van den Berg
Hugo A
HA
Price
David A
DA
Sewell
Andrew K
AK
D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology*; D016827:CD8 Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D015234:HLA-A Antigens / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008969:Molecular Sequence Data; D009154:Mutation; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020349:Surface Plasmon Resonance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D011948:Receptors, Antigen, T-Cell