title: Restricted T-cell receptor beta-chain usage by T cells autoreactive to beta(2)-glycoprotein I in patients with antiphospholipid syndrome.
abstract: We recently identified CD4(+) T cells that are autoreactive to beta(2)-glycoprotein I (beta(2)GPI) and that promote antiphospholipid antibody production in patients with antiphospholipid syndrome (APS). In this study, T-cell receptor (TCR) beta chains of beta(2)GPI-reactive T cells were examined in 8 beta(2)GPI-responders, including 5 patients with APS and 3 healthy subjects, using polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) analysis combined with in vitro stimulation of peripheral blood T cells with recombinant beta(2)GPI. The TCR Vbeta segments that expanded oligoclonally after stimulation with beta(2)GPI varied among responders, but the Vbeta7 and Vbeta8 segments were commonly detected in 6 and 4 beta(2)GPI-responders, respectively. Analysis of the complementarity-determining region 3 sequence of beta(2)GPI-reactive T cells revealed limited diversity, and all Vbeta7(+) TCRs had an amino acid motif of TGxxN/Q or minor variations. The Vbeta8(+) TCRs had another motif, PxAxxD/E. Surprisingly, an identical Vbeta7(+) TCRbeta chain was used by beta(2)GPI-reactive T cells in 3 patients with APS. There was no apparent difference in the TCRbeta usage between APS patients and healthy responders. Some of the Vbeta7(+) TCRs with the TGxxN/Q motif detected by PCR-SSCP analysis were also used by beta(2)GPI-specific CD4(+) T-cell clones responsive to an immunodominant epitope containing the major phospholipid-binding site. Depletion of Vbeta7(+) or Vbeta8(+) T cells from the peripheral blood mononuclear cell cultures significantly inhibited in vitro anti-beta(2)GPI antibody production in response to beta(2)GPI. Our results indicate preferential usage of TCRbeta chains by beta(2)GPI-reactive T cells. These TCRbeta chains can be reasonable targets for TCR-based immunotherapy for patients with APS.
authors.affiliation: Institute for Advanced Medical Research, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takahide
authors.initials: T
authors.lastname: Arai
authors.forename: Junichi
authors.initials: J
authors.lastname: Kaburaki
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
mesh_terms: D000595:Amino Acid Sequence; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D001053:Apolipoproteins / Q000276:immunology; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002999:Clone Cells; D004247:DNA / Q000235:genetics / Q000276:immunology; D019674:Genes, T-Cell Receptor beta; D005838:Genotype; D006023:Glycoproteins / Q000276:immunology*; D006681:HLA-D Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D053482:beta 2-Glycoprotein I
chemical_list: D001053:Apolipoproteins; D006023:Glycoproteins; D006681:HLA-D Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D053482:beta 2-Glycoprotein I; D004247:DNA