Hacquard-Bouder Cécile, Chimenti Maria-Sole, Giquel Benoît, Donnadieu Emmanuel, Fert Ingrid, Schmitt Alain, André Claudine, Breban Maxime
Institut Cochin, Université René Descartes, CNRS (VMR 8104), Paris, INSERM U 567, Paris, France.
Arthritis Rheum. 2007 May;56(5):1478-89. doi: 10.1002/art.22572.
To investigate the molecular mechanism responsible for the reduced capacity of dendritic cells (DCs) from HLA-B27-transgenic rats to form conjugates with naive T cells.
We monitored interactions between DCs derived from HLA-B27-transgenic, HLA-B7-transgenic control, and nontransgenic rats and naive CD4+ T cells. Chemoattraction was studied in Transwell assays, and the formation of an immunologic synapse was examined by videomicroscopy and electron microscopy. Involvement of specific molecules in the defective interaction was examined in antibody-blocking assays.
T cells migrated normally toward B27 DCs, but upon contact, the frequency of T cells undergoing a Ca2+ response was decreased, indicating impaired immunologic synapse formation. The immunologic synapse formed between B27 DCs and T cells appeared to be normal, as assessed by electron microscopy and by the Ca2+ response. Blocking lymphocyte function-associated antigen 1 on T cells or blocking activated leukocyte cell adhesion molecules on DCs inhibited an equivalent proportion of conjugates from forming between B27 or control DCs and T cells, whereas blocking CD86 on DCs and blocking CD28, CD2, or CD4 on T cells inhibited a greater number of conjugates from forming with control DCs, indicating specific involvement of costimulatory molecules in the reduced formation of conjugates with B27 DCs. Mature B27 molecules on the DC surface were responsible for this decreased formation of conjugates.
In the HLA-B27-transgenic rat model of spondylarthropathy, mature B27 molecules expressed by DCs impair the formation of an antigen-independent immunologic synapse with naive CD4+ T cells by interfering with the engagement of costimulatory molecules. This phenomenon could potentially affect the production and/or maintenance of regulatory T cells and contribute to the expansion of pathogenic CD4+ T cells.
研究HLA - B27转基因大鼠树突状细胞（DCs）与初始T细胞形成结合物能力降低的分子机制。
我们监测了来自HLA - B27转基因、HLA - B7转基因对照和非转基因大鼠的DCs与初始CD4 + T细胞之间的相互作用。在Transwell实验中研究趋化作用，并通过视频显微镜和电子显微镜检查免疫突触的形成。在抗体阻断实验中检查特定分子在缺陷相互作用中的参与情况。
T细胞正常向B27 DCs迁移，但接触后，经历Ca2 +反应的T细胞频率降低，表明免疫突触形成受损。通过电子显微镜和Ca2 +反应评估，B27 DCs与T细胞之间形成的免疫突触似乎正常。阻断T细胞上的淋巴细胞功能相关抗原1或阻断DCs上的活化白细胞细胞粘附分子可抑制B27或对照DCs与T细胞之间形成同等比例的结合物，而阻断DCs上的CD86以及阻断T细胞上的CD28、CD2或CD4可抑制与对照DCs形成更多的结合物，表明共刺激分子特异性参与了与B27 DCs结合物形成减少的过程。DC表面的成熟B27分子导致了这种结合物形成减少。
在脊柱关节病的HLA - B27转基因大鼠模型中，DCs表达的成熟B27分子通过干扰共刺激分子的结合，损害了与初始CD4 + T细胞形成抗原非依赖性免疫突触的过程。这种现象可能潜在地影响调节性T细胞的产生和/或维持，并有助于致病性CD4 + T细胞的扩增。
