A novel approach to antigen-specific deletion of CTL with minimal cellular activation using alpha3 domain mutants of MHC class I/peptide complex.
In this study, we have compared the effector functions and fate of a number of human CTL clones in vitro or ex vivo following contact with variant peptides presented either on the cell surface or in a soluble multimeric format. In the presence of CD8 coreceptor binding, there is a good correlation between TCR signaling, killing of the targets, and FasL-mediated CTL apoptosis. Blocking CD8 binding using alpha3 domain mutants of MHC class I results in much reduced signaling and reduced killing of the targets. Surprisingly, however, FasL expression is induced to a similar degree on these CTLs, and apoptosis of CTL is unaffected. The ability to divorce these events may allow the deletion of antigen-specific and pathological CTL populations without the deleterious effects induced by full CTL activation.
Xu
X N
XN
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, OX3 9DS, Oxford, United Kingdom. xiaoning@molbiol.ox.ac.uk
Purbhoo
M A
MA
Chen
N
N
Mongkolsapaya
J
J
Cox
J H
JH
Meier
U C
UC
Tafuro
S
S
Dunbar
P R
PR
Sewell
A K
AK
Hourigan
C S
CS
Appay
V
V
Cerundolo
V
V
Burrows
S R
SR
McMichael
A J
AJ
Screaton
G R
GR
D017209:Apoptosis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053222:Fas Ligand Protein; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D015488:HIV Antigens / Q000235:genetics / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D059948:HLA-B44 Antigen; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology; D016296:Mutagenesis; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins; D001613:beta 2-Microglobulin / Q000235:genetics / Q000276:immunology; D019014:fas Receptor / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D015683:Gene Products, gag; D015488:HIV Antigens; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; C054979:antigen T cell receptor, zeta chain; D001613:beta 2-Microglobulin; D019014:fas Receptor; D054301:gag Gene Products, Human Immunodeficiency Virus; C098952:influenza virus membrane protein (58-66); C054858:p17 protein, Human Immunodeficiency Virus Type 1; C061169:p18 gag protein, Human immunodeficiency virus 1