A novel approach to antigen-specific deletion of CTL with minimal cellular activation using alpha3 domain mutants of MHC class I/peptide complex

X N Xu; M A Purbhoo; N Chen; J Mongkolsapaya; J H Cox; U C Meier; S Tafuro; P R Dunbar; A K Sewell; C S Hourigan; V Appay; V Cerundolo; S R Burrows; A J McMichael; G R Screaton

doi:10.1016/s1074-7613(01)00133-9

A novel approach to antigen-specific deletion of CTL with minimal cellular activation using alpha3 domain mutants of MHC class I/peptide complex

Immunity. 2001 May;14(5):591-602. doi: 10.1016/s1074-7613(01)00133-9.

Authors

X N Xu¹, M A Purbhoo, N Chen, J Mongkolsapaya, J H Cox, U C Meier, S Tafuro, P R Dunbar, A K Sewell, C S Hourigan, V Appay, V Cerundolo, S R Burrows, A J McMichael, G R Screaton

Affiliation

¹ MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, OX3 9DS, Oxford, United Kingdom. [email protected]

PMID: 11371361
DOI: 10.1016/s1074-7613(01)00133-9

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / immunology*
CD8-Positive T-Lymphocytes / immunology
Fas Ligand Protein
Gene Products, gag / genetics
Gene Products, gag / immunology
HIV Antigens / genetics
HIV Antigens / immunology
HLA-A2 Antigen / genetics
HLA-A2 Antigen / immunology*
HLA-B Antigens / genetics
HLA-B Antigens / immunology*
HLA-B44 Antigen
Humans
Influenza A virus / genetics
Influenza A virus / immunology
Lymphocyte Activation / immunology*
Membrane Glycoproteins / immunology
Membrane Proteins / immunology
Mutagenesis
Peptide Fragments / genetics
Peptide Fragments / immunology
Peptides / immunology*
Phosphorylation
Receptors, Antigen, T-Cell / immunology
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / immunology
T-Lymphocytes, Cytotoxic / immunology*
Viral Matrix Proteins / genetics
Viral Matrix Proteins / immunology
Viral Proteins*
beta 2-Microglobulin / genetics
beta 2-Microglobulin / immunology
fas Receptor / immunology
gag Gene Products, Human Immunodeficiency Virus

Substances

FASLG protein, human
Fas Ligand Protein
Gene Products, gag
HIV Antigens
HLA-A2 Antigen
HLA-B Antigens
HLA-B44 Antigen
Membrane Glycoproteins
Membrane Proteins
Peptide Fragments
Peptides
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
Viral Matrix Proteins
Viral Proteins
antigen T cell receptor, zeta chain
beta 2-Microglobulin
fas Receptor
gag Gene Products, Human Immunodeficiency Virus
influenza virus membrane protein (58-66)
p17 protein, Human Immunodeficiency Virus Type 1
p18 gag protein, Human immunodeficiency virus 1