García-Peydró M, Paradela A, Albar J P, Castro J A
Centro de Biología Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientificas), Universidad Autónoma de Madrid, Facultad de Ciencias, Cantoblanco, Madrid, Spain.
J Immunol. 2000 Nov 15;165(10):5680-5. doi: 10.4049/jimmunol.165.10.5680.
Antagonism of allospecific CTL by altered MHC ligands is a potential approach to specific immunomodulation of allogeneic T cell responses in acute graft rejection and graft-vs-host disease. In this study we have analyzed the capacity of peptide analogs of a natural HLA-B27-allospecific CTL epitope to antagonize direct alloreactivity. Alanine scanning demonstrated that positions 4, 5, and 7 of the peptide epitope were critical for allorecognition. A number of relatively conservative substitutions at each of these positions were then tested for their effect on allorecognition and antagonism. All substitutions at position 5 abrogated cytotoxicity. In contrast, a few changes at positions 4 and 7 were tolerated, indicating a limited flexibility of the allospecific CTL in recognition of peptide epitope variants. Most of the substitutions impairing cytotoxicity actually induced antagonism. However, whereas epitope variants with changes at positions 4 and 7 behaved as weak or intermediate antagonists, some of the variants with changes at position 5 antagonized CTL alloreactivity almost completely. The results in this study demonstrate for the first time that antagonism of direct class I-mediated alloreactivity can be achieved by variants of a natural allospecific peptide epitope.
通过改变MHC配体来拮抗同种特异性CTL是在急性移植物排斥反应和移植物抗宿主病中对同种异体T细胞反应进行特异性免疫调节的一种潜在方法。在本研究中，我们分析了天然HLA - B27同种特异性CTL表位的肽类似物拮抗直接同种异体反应性的能力。丙氨酸扫描表明，肽表位的第4、5和7位对于同种异体识别至关重要。然后测试了这些位置上的一些相对保守的取代对同种异体识别和拮抗作用的影响。第5位的所有取代都消除了细胞毒性。相反，第4和7位的一些变化是可以耐受的，这表明同种特异性CTL在识别肽表位变体方面的灵活性有限。大多数损害细胞毒性的取代实际上诱导了拮抗作用。然而，虽然在第4和7位有变化的表位变体表现为弱拮抗剂或中等强度拮抗剂，但在第5位有变化的一些变体几乎完全拮抗CTL同种异体反应性。本研究结果首次证明，天然同种特异性肽表位的变体可以实现对直接I类介导的同种异体反应性的拮抗作用。
