Chapatte Laurence, Servis Catherine, Valmori Danila, Burlet-Schiltz Odile, Dayer Johanna, Monsarrat Bernard, Romero Pedro, Lévy Frédéric
Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Ch. des Boveresses 155, CH-1066 Epalinges, Switzerland.
J Immunol. 2004 Nov 15;173(10):6033-40. doi: 10.4049/jimmunol.173.10.6033.
The melanoma-associated protein Melan-A contains the immunodominant CTL epitope Melan-A(26/27-35)/HLA-A*0201 against which a high frequency of T lymphocytes has been detected in many melanoma patients. In this study we show that the in vitro degradation of a polypeptide encompassing Melan-A(26/27-35) by proteasomes produces both the final antigenic peptide and N-terminally extended intermediates. When human melanoma cells expressing the corresponding fragments were exposed to specific CTL, those expressing the minimal antigenic sequence were recognized more efficiently than those expressing the N-terminally extended intermediates. Using a tumor-reactive CTL clone, we confirmed that the recognition of melanoma cells expressing an N-terminally extended intermediate of Melan-A is inefficient. We demonstrated that the inefficient cytosolic trimming of N-terminally extended intermediates could offer a selective advantage for the preferred presentation of Melan-A peptides directly produced by the proteasomes. These results imply that both the proteasomes and postproteasomal peptidases limit the availability of antigenic peptides and that the efficiency of presentation may be affected by conditions that alter the ratio between fully and partially processed proteasomal products.
黑色素瘤相关蛋白Melan - A含有免疫显性CTL表位Melan - A(26/27 - 35)/HLA - A*0201，在许多黑色素瘤患者中已检测到针对该表位的高频T淋巴细胞。在本研究中，我们发现蛋白酶体对包含Melan - A(26/27 - 35)的多肽进行体外降解时，会产生最终的抗原肽和N端延伸的中间体。当表达相应片段的人黑色素瘤细胞暴露于特异性CTL时，表达最小抗原序列的细胞比表达N端延伸中间体的细胞更有效地被识别。使用肿瘤反应性CTL克隆，我们证实对表达Melan - A的N端延伸中间体的黑色素瘤细胞的识别效率低下。我们证明，N端延伸中间体的胞质低效修剪可为蛋白酶体直接产生的Melan - A肽的优先呈递提供选择性优势。这些结果表明，蛋白酶体和蛋白酶体后肽酶均会限制抗原肽的可用性，并且呈递效率可能会受到改变完全和部分加工的蛋白酶体产物之间比例的条件的影响。
