Identification of HLA class II-restricted H-Y-specific T-helper epitope evoking CD4+ T-helper cells in H-Y-mismatched transplantation.
BACKGROUND
Stem-cell grafts between HLA-identical siblings are less likely to succeed when there is a sex mismatch. This lack of success can be interpreted as enhanced activity directed against minor histocompatibility antigens encoded by the Y chromosome (H-Y). So far, in man, only cytotoxic T lymphocytes (CTLs) specific for several minor histocompatibility antigens have been reported. We aimed to identify and clarify the role of MHC class II-restricted H-Y-specific T-helper cells in these transplant settings.


METHODS
H-Y-specific MHC class II-restricted CD4+ T cells were isolated from blood of a female patient who rejected an HLA-identical male stem-cell transplant. By molecular cloning of H-Y genes and functional T-helper experiments, we elucidated antigen specificity and the functional properties of these H-Y-specific T-helper cells.


RESULTS
CD4+ T-helper cells recognise the Y gene-encoded peptide VIKVNDTVQI presented by HLA-DRbeta3*0301. These T-helper cells mature dendritic cells and enhance expansion of minor histocompatibility antigen-specific MHC class I-restricted CD8+ CTLs.


CONCLUSIONS
Characterisation of an MHC class II-restricted H-Y epitope that evoked CD4+ T-helper responses adds a novel cellular component to the alloimmune response against Y chromosome-encoded minor histocompatibility antigens. This component completes the H-Y-directed alloimmune response and aids understanding of the poorer outcome of sex-mismatched transplants.
Spierings
Eric
E
Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Post-box 9600, 2300 RC, Leiden, Netherlands. eric.spierings@lumc.nl
Vermeulen
Corine J
CJ
Vogt
Mario H
MH
Doerner
Lucie E E
LE
Falkenburg
J H Frederik
JH
Mutis
Tuna
T
Goulmy
Els
E
D000328:Adult; D000741:Anemia, Aplastic / Q000601:surgery; D015704:CD4 Antigens / Q000276:immunology*; D041322:Chromosomes, Human, Y / Q000276:immunology; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D024282:Genes, sry / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006182:H-Y Antigen / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D008297:Male; D008912:Minor Histocompatibility Loci / Q000276:immunology; D019849:Sex Determination Processes; D012737:Sex Factors; D033581:Stem Cell Transplantation; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D014181:Transplantation Immunology / Q000276:immunology*
D015704:CD4 Antigens; D018984:Epitopes, T-Lymphocyte; D006182:H-Y Antigen; D000949:Histocompatibility Antigens Class II