Stanková J, Hoskin D W, Roder J C
Division of Molecular Immunology and Neurobiology, Mount Sinai Hospital Research Institute, Toronto, Ontario, Canada.
Cell Immunol. 1989 Jun;121(1):13-29. doi: 10.1016/0008-8749(89)90002-6.
Antibodies specific for the CD3 complex have the capacity to both stimulate and inhibit a variety of T cell functions. We show here that a monoclonal antibody to the epsilon chain of CD3 can induce efficient non-MHC-restricted cytolytic activity in murine lymphocytes with peak activity occurring after 48 hr of incubation. In a panel of targets, the anti-CD3-activated effectors lysed tumor cells but not normal lymphoblasts. Cytolysis was not dependent on the presence of the antibody in the cytolytic assay. Moderate to high cytolytic activity was elicited from lymph nodes, spleen, and thymus by anti-CD3 treatment in vitro, whereas only low activity was apparent in bone marrow. The precursors of anti-CD3-activated cells consisted largely of mature T cells, although a smaller component of immature T cells was also involved. Thus, separation of thymocytes based on adhesion to peanut agglutinin revealed that both positive (immature) and negative (mature) fractions could be activated, while cytotoxic pretreatment of spleen cells with an antibody (J11d) to immature T cells before anti-CD3 activation significantly decreased the resulting cytotoxicity. The majority of precursors in spleen were Thy 1+ and CD8+ and/or AGM1+. Antibody depletion studies showed that the effector cells have both a T and a NK component consisting of Thy 1+, CD5+, CD8+, CD4-, and AGM1- cells and Thy 1-, CD5-, CD8-, CD4-, and AGM1+ cells, respectively. The production of significant amounts of IL-2 and TNF in culture following anti-CD3 treatment, along with the synergistic effect of exogenously added IL-2, suggests that one or both of the effector cell types could be induced by lymphokines. The intraperitoneal administration of the anti-CD3 antibody induces cytolytic activity in vivo. Therefore, the direct activation of cytolysis by anti-CD3 antibody and the additional effects, both direct and synergistic, of lymphokines produced by the activated lymphocytes could conceivably provide a potent anti-tumor therapy.
针对CD3复合物的特异性抗体具有刺激和抑制多种T细胞功能的能力。我们在此表明，一种针对CD3 ε链的单克隆抗体可在小鼠淋巴细胞中诱导高效的非MHC限制性细胞溶解活性，在孵育48小时后活性达到峰值。在一组靶细胞中，抗CD3激活的效应细胞可裂解肿瘤细胞，但不能裂解正常淋巴母细胞。细胞溶解不依赖于细胞溶解试验中抗体的存在。体外抗CD3处理可从淋巴结、脾脏和胸腺中诱导出中度至高细胞溶解活性，而在骨髓中仅表现出低活性。抗CD3激活细胞的前体主要由成熟T细胞组成，尽管也有较小部分未成熟T细胞参与。因此，基于对花生凝集素的黏附分离胸腺细胞显示，阳性（未成熟）和阴性（成熟）部分均可被激活，而在抗CD3激活前用针对未成熟T细胞的抗体（J11d）对脾细胞进行细胞毒性预处理可显著降低产生的细胞毒性。脾脏中的大多数前体是Thy 1 +、CD8 +和/或AGM1 +。抗体清除研究表明，效应细胞既有T细胞成分又有NK细胞成分，分别由Thy 1 +、CD5 +、CD8 +、CD4 -和AGM1 -细胞以及Thy 1 -、CD5 -、CD8 -、CD4 -和AGM1 +细胞组成。抗CD3处理后培养物中大量IL - 2和TNF的产生，以及外源性添加IL - 2的协同作用，表明效应细胞类型中的一种或两种可能由淋巴因子诱导。腹腔注射抗CD3抗体可在体内诱导细胞溶解活性。因此，抗CD3抗体直接激活细胞溶解以及活化淋巴细胞产生的淋巴因子的直接和协同附加效应，理论上可提供一种有效的抗肿瘤治疗方法。
