RESUMO
Human and murine T cells that specifically recognize CD1d and produce IL-4 and IFN-gamma play a role in immunoregulation and tumor rejection. In the mouse, most CD1d1-reactive T cells described express an invariant Valpha14-Jalpha281 TCR associated with TCR beta-chains of limited diversity. Similarly, human CD1d-reactive T cells express a highly restricted TCR repertoire. Here we report the unexpected result that in mice immunized with CD1d1-bearing transfectant cells, a diverse repertoire of TCRs was expressed by CD1d1-reactive T cell clones isolated by limiting dilution without preselection for NK1 expression. Only 3 of 10 CD1d1-reactive T cell clones expressed the invariant Valpha14-Jalpha281 TCRalpha rearrangement. T cells expressing Valpha10, -11, -15, and -17, and having non-germline-encoded nucleotides resulting in diverse V-J junctions were identified. Like CD1d1-reactive T cells expressing the invariant Valpha14-Jalpha281 TCR alpha-chain, CD1d1-reactive clones with diverse TCRs produced both Type 1 (IFN-y) and Type 2 (IL-4, IL-10) cytokines. This establishes the existence of significant diversity in the TCRs directly reactive to the CD1d1 protein. Our findings reveal that CD1d interacts with a broad array of TCRs, suggesting substantial redundancy and flexibility of the immune system in providing T cells serving the role(s) mediated by CD1d reactivity.
Assuntos
Antígenos CD1/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/metabolismo , Sequência de Aminoácidos , Animais , Antígenos CD1/genética , Antígenos CD1/imunologia , Linhagem Celular , Células Clonais/metabolismo , Citocinas/biossíntese , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/imunologia , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/imunologia , Linfoma de Células T , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T/genética , Células Tumorais CultivadasAssuntos
Proteínas do Sistema Complemento/fisiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Alelos , Animais , Complexo Antígeno-Anticorpo/fisiologia , Autoanticorpos/análise , Complemento C4a/genética , Complemento C4a/imunologia , Proteínas do Sistema Complemento/deficiência , Deleção de Genes , Humanos , Doenças do Complexo Imune/etiologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/genética , Camundongos/metabolismoRESUMO
OBJECTIVE: To investigate the predisposing role of major histocompatibility complex (MHC) genes to autoantibody production and clinical manifestations comparing French Canadian and Non-French Canadian Caucasians with systemic lupus erythematosus (SLE) METHODS: Ninety-one Caucasian patients with SLE were studied. Clinical manifestations, autoantibody expression and HLA-A, B, (serology), DR, DQ and C4A gene deletion (restriction fragment length polymorphism [RFLP] typing) were determined. RESULTS: Photosensitivity was present in all SLE subjects with anti-Ro antibodies (P=0.001, RR=13.1, CI=1.8, 564). Photosensitivity was further associated with the HLA-A1, C4A gene deletion haplotype. More strikingly, C4A gene deletion was associated with anti-Ro (P=0.008, RR=4.6, CI=1.4, 16.2) and anti-La (P=0.02, RR=11.7, CI=1.4, 549) autoantibodies. This relationship was also significant for anti-Ro antibody in the French Canadian patients (P=0.01, RR=21.3, CI=1.7, 105.3). In contrast, anti-dsDNA autoantibodies were negatively associated with photosensitivity (P=0.02, RR=0.3, CI=0.07, 0.8) and correlated with HLA-DR15 (P=0.006, RR=4.2, CI=1.5, 12.8) and Dw2 (P=0.009, RR=3.9, CI=1.4, 11.9). CONCLUSION: C4A gene deletion has a previously unrecognized powerful association with anti-Ro and anti-La autoantibodies. These results support the concept of divergent MHC gene associations with autoantibody expression and emphasize the influence of ethnicity on the immunogenetic study of SLE.
