Wagner N, Engel P, Vega M, Tedder T F
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA.
J Immunol. 1994 Jun 1;152(11):5275-87.
Engagement of lymphocyte MHC class I and class II Ags activates an array of intracellular signal transduction pathways that up-regulates the activity of cell-surface adhesion receptors, resulting in homotypic cell-cell aggregation. In this study, engagement of MHC class I and class II molecules with specific mAbs was shown to also inhibit lymphocyte homotypic adhesion. Two mAbs reactive with class II Ag, homotypic adhesion blocking mAb (HAB)-2, and HAB-3, and one mAb reactive with class I Ag, HAB-4, were generated that inhibited homotypic adhesion of activated lymphocytes and B and T cell lines at concentrations as low as 0.1 microgram/ml. Binding of these mAbs resulted in heterologous desensitization of other surface signal transduction molecules as homotypic adhesion induced through class I, class II, CD19, CD20, CD39, CD40, Leu-13, and PMA was also inhibited. The spontaneous adhesion exhibited by some cell lines was also abrogated by binding of these mAbs. Abs that either induced, blocked, or had no effect on adhesion bound to distinct epitopes on class I, whereas the anti-class II mAbs recognized either distinct or overlapping epitopes. Thus, engagement of distinct epitopes on MHC molecules can result in homologous or heterologous desensitization of cell-surface signaling molecules. The induction or inhibition of homotypic adhesion through class I molecules did not require the presence of the cytoplasmic domain, as deletion of this portion of the class I molecule had no effect. In contrast, the transmembrane region was essential for signal transduction as the mAbs binding to a chimeric molecule in which the transmembrane and cytoplasmic domains of class I were exchanged with those of the HB15 molecule did not induce or inhibit homotypic adhesion. Although this report is the first demonstration that homotypic adhesion can be influenced in a negative manner through MHC molecules, these findings demonstrate a considerable level of cross-talk between MHC molecules and other cell-surface receptor systems and their signal transduction pathways, and suggests that MHC class I and class II molecules may serve important roles in the regulation of adhesive events during lymphocyte activation.
淋巴细胞MHC I类和II类抗原的结合激活了一系列细胞内信号转导途径，这些途径上调细胞表面黏附受体的活性，导致同型细胞间聚集。在本研究中，MHC I类和II类分子与特异性单克隆抗体的结合也被证明可抑制淋巴细胞同型黏附。产生了两种与II类抗原反应的单克隆抗体，即同型黏附阻断单克隆抗体（HAB）-2和HAB-3，以及一种与I类抗原反应的单克隆抗体HAB-4，它们在低至0.1微克/毫升的浓度下就能抑制活化淋巴细胞以及B和T细胞系的同型黏附。这些单克隆抗体的结合导致其他表面信号转导分子的异源脱敏，因为通过I类、II类、CD19、CD20、CD39、CD40、Leu-13和佛波酯诱导的同型黏附也受到抑制。这些单克隆抗体的结合还消除了一些细胞系表现出的自发黏附。诱导、阻断或对黏附无影响的抗体与I类分子上不同的表位结合，而抗II类单克隆抗体识别不同或重叠的表位。因此，MHC分子上不同表位的结合可导致细胞表面信号分子的同源或异源脱敏。通过I类分子诱导或抑制同型黏附并不需要细胞质结构域的存在，因为缺失I类分子的这一部分没有影响。相比之下，跨膜区对于信号转导至关重要，因为与一种嵌合分子结合的单克隆抗体，其中I类分子的跨膜区和细胞质结构域与HB15分子的进行了交换，该单克隆抗体既不诱导也不抑制同型黏附。虽然本报告首次证明同型黏附可通过MHC分子以负面方式受到影响，但这些发现表明MHC分子与其他细胞表面受体系统及其信号转导途径之间存在相当程度的相互作用，并表明MHC I类和II类分子可能在淋巴细胞活化过程中黏附事件的调节中发挥重要作用。
