CD8+T-cell specificity is compromised at a defined MHCI/CD8 affinity threshold.
The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity.
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Tamsin
T
Dockree
Faculty of Health Sciences, University of Bristol, Bristol, UK.
Christopher J
CJ
Holland
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Mathew
M
Clement
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Kristin
K
Ladell
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
James E
JE
McLaren
Mathematics Institute, University of Warwick, Coventry, UK.
Hugo A
HA
van den Berg
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Emma
E
Gostick
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Kelly
K
L Miners
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
Sian
S
Llewellyn-Lacey
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.
John S
JS
Bridgeman
Institute of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK.
Stephen
S
Man
Faculty of Health Sciences, University of Bristol, Bristol, UK.
Mick
M
Bailey
Cellular Immunology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
Scott R
SR
Burrows
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.|Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
David A
DA
Price
Faculty of Health Sciences, University of Bristol, Bristol, UK.
Linda
L
Wooldridge
D016827:CD8 Antigens / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002462:Cell Membrane / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000378:metabolism
D016827:CD8 Antigens; D015395:Histocompatibility Antigens Class I; D010455:Peptides
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