Abnormal T-cell function in B-cell chronic lymphocytic leukaemia
Abnormal T-cell function in B-cell chronic lymphocytic leukaemia
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DOI：
10.1080/1042819021000029993
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发表时间：
2003-01-01
影响因子：
2.6
通讯作者：
Prentice, AG
中科院分区：
文献类型：
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作者：
Scrivener, S;Goddard, RV;Prentice, AG
B细胞慢性淋巴细胞白血病（B-CLL）中T细胞功能障碍的证据越来越多，这可能有助于疾病的病因学和进展。绝对CD 8+淋巴细胞增多与疾病进展相关，并且CD 4和CD 8的低表达（如在自身免疫性疾病中发现的）与其他表面分子的异常表达相关。尽管在B-CLL血清中培养时T细胞表面活化标志物CD 25和CD 152的表达可能增加，但对常见有丝分裂原PHA和PWM的反应降低。这和过量的CD 8细胞可以部分解释在B-CLL中T细胞与B细胞产生免疫球蛋白的可变合作。在T细胞与抗原呈递细胞相互作用的情况下，B-CLL B细胞是较差的抗原呈递细胞。但是T细胞本身具有该过程所必需的许多抗原和配体的表达的显著异常。特别是，它们表现出低亲和力和非特异性粘附分子LFA-1和ICAM-1的可变表达，TCR库的可变、克隆限制和偏斜表达，（暗示可能由CLL抗原引起的重复抗原刺激），降低CD 28和CD 152表达（意味着启动或停止免疫应答的能力受损）和降低的IL 2和CD 25（IL 2 R）表达（对于维持和扩大T细胞对抗原呈递的应答的正反馈是关键的）。尽管B-CLL中T细胞产生IL 2和其它细胞因子可能受损，抗凋亡细胞因子IL 4的产生是不可能的，并且可能存在能够释放IL 4的独特和扩增的CD 8/CD 30细胞亚群。这种T细胞亚群与体内恶性B细胞的关系尚不清楚。然而，作为CD 4 +/CD 152 +/CCR 4+的T细胞响应于由恶性B细胞产生的趋化因子CCL 22（对受体CCR 4特异性）而选择性地在体外迁移，并且总是在来自B-CLL患者的骨髓和淋巴结中的恶性细胞中看到。其他异常的细胞因子分泌的描述。这些研究结果表明，T细胞在B-CLL可能无法启动，维持和完成免疫反应的恶性B细胞和其他抗原，并可能直接参与维持肿瘤。然而，自体肿瘤特异性细胞毒性已经在体外显示，并且识别肿瘤衍生的重链片段的T细胞在体内循环。如果任何性质的过继免疫疗法要在B-CLL中取得成功，则需要优化这些CTL应答的操作来克服这种疾病中的深刻和可变的T细胞功能障碍。
There is increasing evidence of T cell dysfunction in B cell chronic lymphocytic leukaemia (B-CLL) which may contribute to the aetiology and progress of the disease. An absolute CD8+ lymphocytosis correlates with disease progression and low expression of CD4 and CD8 (as found in autoimmune disease) is seen with abnormal expression of other surface molecules. Although the expression of T cell surface activation markers, CD25 and CD152, may be increased on culture in B-CLL serum, response to the common mitogens, PHA and PWM, is reduced. This and the excess of CD8 cells may explain partly the variable cooperation of T cells with B cell production of immunoglobulin in B-CLL. In the context of T cell cross-talk with antigen presenting cells, B-CLL B cells are poor antigen presenters. But the T cells themselves have significant abnormalities of expression of the many antigens and ligands necessary for this process. In particular, they exhibit variable expression of the low affinity and non-specific adhesion molecules LFA-1 and ICAM-1, variable, clonally restricted and skewed expression of the TCR repertoire (implying repeated antigenic stimulation possibly by CLL antigens), reduced CD28 and CD152 expression (implying impairment of ability to start or stop an immune response) and reduced IL2 and CD25 (IL2 R) expression (critical for positive feed-back in maintenance and expansion of the T cell response to antigen presentation).Although the production of IL2 and other cytokines by the T cell in B-CLL may be impaired, production of the anti-apoptotic cytokine IL4 is not and there may be a unique and expanded subset of CD8/CD30 cells capable of releasing IL4. The relationship of this T cell subset to the malignant B cell in vivo is unknown. However, T cells which are CD4+/CD152+/CCR4+ migrate selectively in vitro in response to the chemokine CCL22 (specific for the receptor CCR4) produced by the malignant B cells and are always seen amongst the malignant cells in bone marrow and lymph nodes from B-CLL patients. Other abnormalities of cytokine secretion are described.These findings suggest that the T cell in B-CLL may be unable to start, maintain and complete an immune response to the malignant B cell and other antigens and may be involved directly in sustaining the tumour. However, autologous tumour specific cytotoxicity has been shown in vitro and T cells which recognise tumour-derived heavy chain fragments circulate in vivo . If adoptive immunotherapy of any nature is to succeed in B-CLL, manipulation to optimise these CTL responses is needed to overcome the profound and variable T cell dysfunction in this disease.