Missing HLA class I expression on Daudi cells unveils cytotoxic and proliferative responses of human gammadelta T lymphocytes.
The major subset of human blood gammadelta T lymphocytes expresses the variable-region genes Vgamma9 and Vdelta2. These cells recognize non-peptidic phosphoantigens that are present in some microbial extracts, as well as the beta(2)-microglobulin-deficient Burkitt's lymphoma Daudi. Most cytotoxic human Vgamma9/Vdelta2 T cells express inhibitory natural killer cell receptors for HLA class I that downmodulate the responses of the gammadelta T lymphocytes against HLA class I expressing cells. In this study we show that transfection of the human beta(2)-microglobulin cDNA into Daudi cells markedly inhibits the cytotoxic and proliferative responses of human Vgamma9/Vdelta2 T cells. This provides direct evidence that the "innate" specificity of human Vgamma9/Vdelta2 T-lymphocytes for Daudi cells is uncovered by the loss of beta(2)m by Daudi. However, Daudi cells that express HLA class I in association with mouse beta(2)m at the cell surface are recognized by human Vgamma9/Vdelta2 T cells close to the same degree as the parental HLA class I deficient Daudi cell line. Thus, proper conformation of the HLA class I molecules is required for binding to natural killer cell receptors. Cloning of the HLA class I A, B, and C molecules of Daudi cells and transfer of the individual HLA class I molecules of Daudi cells into the HLA class I deficient recipient cell lines.221 and C1R demonstrate that for some human gammadelta T-cell clones cytolysis can be entirely inhibited by single HLA class I alleles while for other clones single HLA class I alleles only partially inhibit cytotoxicity. Thus, most human Vgamma9/Vdelta2 T cells represent a population of killer cells that evolved like NK cells to destroy target cells that have lost expression of individual HLA class I molecules but with a specificity that is determined by the Vgamma9/Vdelta2 TCR.
Division of Clinical Pharmacology, Department of Medicine, University of Munich, Germany.
Simon
S
Rothenfusser
Armin
A
Buchwald
Sylvia
S
Kock
Soldano
S
Ferrone
Paul
P
Fisch
D000483:Alleles; D002478:Cells, Cultured; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D006680:HLA Antigens / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006825:Hybridomas; D007135:Immunoglobulin Variable Region / Q000235:genetics; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis* / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics; D054340:Receptors, KIR; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014407:Tumor Cells, Cultured; D001613:beta 2-Microglobulin / Q000235:genetics
D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D007135:Immunoglobulin Variable Region; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D001613:beta 2-Microglobulin