Bank I, Cohen L, Kneller A, De Rosbo N K, Book M, Ben-Nun A
Department of Medicine F, Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Hashomer, Israel.
Scand J Immunol. 2003 Jul;58(1):89-98. doi: 10.1046/j.1365-3083.2003.01272.x.
We previously found that the peripheral blood (PB) mononuclear cells (MCs) (PBMCs) of a patient with chronic neutropenia contained an expanded population of cytotoxic CD8+ T cells using a variable (V) region delta1 gene product in the T-cell receptor-alpha (TCR-alpha) polypeptide [Vdelta1-constant(C)alpha+ T cells]. Sequencing of polymerase chain reaction (PCR) amplification products have now revealed a productive Vdelta1/joining (J)alphaIGRJa03/Calpha rearrangement of the TCR-alpha gene, predominantly associated with a Vbeta16/Dbeta2.1/Jbeta2.1/Cbeta2 TCR-beta gene, in these cells. Furthermore, we detected a markedly deficient proliferative response of the patient PBMCs to triggering with monoclonal antibodies (MoAbs) to the CD3 molecule, contrasting with a substantial response to the Vbeta3, 12, 14, 15, 17 and 20-specific staphylococcal enterotoxin B (SEB) superantigen, suggesting defective TCR-mediated activation of the Vdelta1+/Vbeta16+ clone. Moreover, whereas triggering of Vdelta1- T cells cultured with interleukin-2 (IL-2) by MoAb to the CD3 molecule enhanced proliferation, Vdelta1-Calpha+ T cells were inhibited by MoAbs to either CD3 or Vdelta1. Vdelta1-Calpha+ T-cell clones spontaneously secrete interferon-gamma (IFN-gamma) and were further induced to release tumour necrosis factor (TNF-alpha) when triggered by anti-CD3 plus phorbol ester. Aberrant signalling by the clonotypic TCR together with the functional properties of the CD8+ Vdelta1+/Vbeta16+ clone may thus contribute to the immunohaematological abnormalities observed in this patient.
我们之前发现，一名慢性中性粒细胞减少症患者的外周血（PB）单个核细胞（MCs）（PBMCs）中，使用T细胞受体α（TCR-α）多肽中的可变（V）区δ1基因产物，含有一群扩增的细胞毒性CD8⁺T细胞[Vδ1恒定（C）α⁺T细胞]。聚合酶链反应（PCR）扩增产物的测序现已揭示，在这些细胞中，TCR-α基因发生了有效的Vδ1/连接（J）αIGRJa03/Cα重排，主要与Vβ16/Dβ2.1/Jβ2.1/Cβ2 TCR-β基因相关。此外，我们检测到该患者PBMCs对用抗CD3分子单克隆抗体（MoAbs）触发的增殖反应明显不足，这与对Vβ3、12、14、15、17和20特异性葡萄球菌肠毒素B（SEB）超抗原的强烈反应形成对比，提示Vδ1⁺/Vβ16⁺克隆的TCR介导的激活存在缺陷。此外，用抗CD3分子MoAb触发培养于白细胞介素-2（IL-2）中的Vδ1⁻T细胞可增强增殖，而Vδ1-Cα⁺T细胞则被抗CD3或抗Vδ1的MoAbs抑制。Vδ1-Cα⁺T细胞克隆自发分泌干扰素-γ（IFN-γ），当用抗CD3加佛波酯触发时，会进一步诱导释放肿瘤坏死因子（TNF-α）。因此，克隆型TCR的异常信号传导以及CD8⁺Vδ1⁺/Vβ16⁺克隆的功能特性可能导致了该患者所观察到的免疫血液学异常。
