Differential requirements for TCR down-regulation induced by anti-CD3 antibody and superantigen

Abstract

세포 표면에는 외부환경인자와 상호작용을 하기 위한 수용체가 존재한다. 수용체가 리간드라는 외부환경인자와 결합을 하게 되면 수용체가 세포 표면으로부터 세포 내부로 이동하는 과정이 일어난다. 항CD3단일클론항체와 수퍼항원은 T 림프구 수용체의 세포내 이입 과정을 유도하는 리간드들이다. 수용체의 세포내 이입 과정은 세포 신호 전달 과정을 동반하는데, 이 과정의 일부를 억제하였을 때, 항CD3단일클론항체와 수퍼항원이 세포내 이입 과정을 유도하는 데 있어서 억제되는 정도의 차별화가 이루어졌다. 그뿐만 아니라 두 리간드가 세포내 이입과정을 유도할 때, T 림프구 수용체의 일부를 이루는 단백질의 분해 양상도 달랐다. 이로써 두 리간드가 T 림프구 세포내 이입 과정을 조절하는 데 있어서 서로 다른 세포 신호 전달 과정을 필요로 할 것이라고 생각되었고, 이 같은 생각은 T 림프구 수용체를 구성하는 단백질의 최종 분해 여부의 차별화로 뒷받침 될 수 있다. ; TCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. It is known that two distinct pathways exist for down-regulation of the TCR. One pathway is activated following TCR ligation and is dependent on tyrosine phosphorylation. The other pathway is dependent on protein kinase C (PKC)-mediated activation of the CD3γ di-leucine-based receptor-sorting motif. Although TCR down-regulation induced by anti-CD3 antibody or superantigen has been known to ligand-induced down-regulation distinct from PKC-induced down-regulation, the present study shows that the two ligands have differential requirements for TCR down-regulation. Anti-CD3 antibody-induced TCR down-regulation was dependent on PTK activation and tyrosine phosphorylation. Superantigen-induced TCR down-regulation was inhibited by latrunculin B implying that actin cytoskeleton was involved in the down-regulation. Furthermore, when TCR down-regulation induced by each ligand was subjected to conditions that selectively inhibit clathrin-mediated endocytosis, TCR down-regulation stimulated by anti-CD3 antibody was severely impaired. In contrast, superantigen-induced TCR down-regulation was only slightly inhibited. These results indicate that clathrin-mediated endocytosis is the predominant pathway for anti-CD3 antibody-induced TCR down-regulation. Consistent with this idea, the fate of TCR was also different when stimulated with each ligand. The degradation of CD3ζ was induced only by anti-CD3 antibody. These results are discussed with respect to the differential requirements for TCR down-regulation and in consequence the use of different endocytic machineries in response to the two stimuli.