title: Existence of MHC class I-restricted alloreactive CD4+ T cells reacting with peptide transporter-deficient cells.
abstract: It is generally accepted that as the result of positive thymic selection, CD8-expressing T cells recognize peptide antigens presented in the context of MHC class I molecules and CD4-expressing T cells interact with peptide antigens presented by MHC class II molecules. Here we report the generation of TCRalpha/beta(+), CD3(+), CD4(+), CD8(-), MHC class I-restricted alloreactive T-cell clones which were induced using peripheral blood mononuclear cells from healthy individuals following in vitro stimulation with transporter associated with antigen processing (TAP)-deficient cell lines T2. The CD4(+) T-cell clones showed an HLA-A2.1-specific proliferative response against T2 cells which was inhibited by anti-CD3 and anti-CD4 monoclonal antibodies. These results suggest that interaction of the TCR with peptide-bound HLA class I molecules contributes to antigen-specific activation of these co-receptor-mismatched T-cell clones. Antigen recognition by alloreactive MHC class I-restricted CD4(+) T cells was inhibited by removing peptides bound to HLA molecules on T2 cells suggesting that the alloreactive CD4(+) T cells recognize peptides that bind in a TAP-independent manner to HLA-A2 molecules. The existence of such MHC class I-restricted CD4(+) T cells which can recognize HLA-A2 molecules in the absence of TAP function may provide a basis for the development of immunotherapy against TAP-deficient tumor variants which would be tolerant to immunosurveillance by conventional MHC class I-restricted cytotoxic lymphocytes.
authors.affiliation: Department of Pathology, Asahikawa Medical College, 2-1-1-1 Midorigaoka Higashi, Asahikawa, 078-8510, Japan. hiroya@asahikawa-med.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: N
authors.initials: N
authors.lastname: Aoki
authors.forename: K
authors.initials: K
authors.lastname: Sato
authors.forename: E
authors.initials: E
authors.lastname: Celis
authors.forename: M
authors.initials: M
authors.lastname: Katagiri
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002455:Cell Division; D002460:Cell Line; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D017252:CD3 Complex; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D007519:Isoantigens; C073119:TAP1 protein, human; D015847:Interleukin-4