Crowley N J, Darrow T L, Quinn-Allen M A, Seigler H F
Department of Surgery, Duke University Medical Center, Durham, NC 27710.
J Immunol. 1991 Mar 1;146(5):1692-9.
Autologous melanoma-specific CTL recognize a common tumor-associated Ag (TAA) in the context of HLA class I antigens. We have demonstrated that HLA-A2 can be a restricting Ag and, in T cell lines homozygous for HLA-A2, that CTL can be generated by stimulation with HLA-A2 allogeneic melanomas. In the current study, we have investigated T cell lines from patients who are heterozygous at HLA-A region locus, to determine the relative importance of each A-region allele in this MHC-restricted recognition of tumor. We have shown that HLA-A1 can be a restricting Ag, and that allogeneic melanomas expressing HLA-A1 can substitute for the autologous tumor in the generation of HLA-A1-restricted CTL. However, when T cell lines express both HLA-A1 and HLA-A2, the HLA-A2 allele governed restriction of the melanoma TAA. Three autologous-stimulated HLA-A1, A2 CTL lines all demonstrated restriction by the HLA-A2 allele, when examined in cytotoxicity assays, cold-competition assays, and proliferation assays. There was no evidence of restriction by the second HLA-allele, HLA-A1. Although the autologous-stimulated CTL use a single A-region allele for tumor recognition, the autologous HLA-A1, A2 tumors are lysed by both HLA-A1-restricted and HLA-A2-restricted CTL. The dominance of restricting alleles was further demonstrated when HLA-matched allogeneic melanomas were used as the stimulating tumor to generate tumor-specific CTL. Stimulation of the heterozygous (HLA-A1, A2) lymphocytes with HLA-A2-matched allogeneic melanomas resulted in CTL specific for the autologous tumor, and restricted by the HLA-A2 Ag. However, stimulation with an HLA-A1-matched allogeneic melanoma failed to induce tumor-specific CTL restricted by the HLA-A1 Ag. The data suggest there is a dominance of HLA-A region Ag at the level of the T cell, such that only one is restricting in the recognition of the autologous melanoma. At the level of the tumor, however, the TAA is expressed in the context of both HLA-A region alleles. We can generate specific CTL from lymph node cells or PBL and HLA-A region matched allogeneic melanomas; however, because most patients are heterozygous at the HLA-A region locus, an understanding of the dominant restricting alleles must be obtained so that an appropriately matched allogeneic melanoma can be selected.
自体黑色素瘤特异性CTL在HLA I类抗原的背景下识别一种常见的肿瘤相关抗原（TAA）。我们已经证明HLA - A2可以是一种限制性抗原，并且在HLA - A2纯合的T细胞系中，通过用HLA - A2同种异体黑色素瘤刺激可以产生CTL。在当前的研究中，我们研究了来自HLA - A区域位点杂合的患者的T细胞系，以确定每个A区域等位基因在这种MHC限制性肿瘤识别中的相对重要性。我们已经表明HLA - A1可以是一种限制性抗原，并且表达HLA - A1的同种异体黑色素瘤可以在产生HLA - A1限制性CTL中替代自体肿瘤。然而，当T细胞系同时表达HLA - A1和HLA - A2时，HLA - A2等位基因决定了黑色素瘤TAA的限制性。在细胞毒性试验、冷竞争试验和增殖试验中检测时，三个自体刺激的HLA - A1、A2 CTL系均显示受HLA - A2等位基因的限制。没有证据表明第二个HLA等位基因HLA - A1具有限制性。尽管自体刺激的CTL使用单个A区域等位基因进行肿瘤识别，但自体HLA - A1、A2肿瘤可被HLA - A1限制性和HLA - A2限制性CTL裂解。当使用HLA匹配的同种异体黑色素瘤作为刺激肿瘤来产生肿瘤特异性CTL时，限制性等位基因的优势进一步得到证明。用HLA - A2匹配的同种异体黑色素瘤刺激杂合（HLA - A1、A2）淋巴细胞会产生针对自体肿瘤的CTL，并受HLA - A2抗原的限制。然而，用HLA - A1匹配的同种异体黑色素瘤刺激未能诱导受HLA - A1抗原限制的肿瘤特异性CTL。数据表明在T细胞水平上HLA - A区域抗原有优势，以至于在自体黑色素瘤的识别中只有一个起限制作用。然而，在肿瘤水平上，TAA在两个HLA - A区域等位基因的背景下表达。我们可以从淋巴结细胞或外周血淋巴细胞以及HLA - A区域匹配的同种异体黑色素瘤中产生特异性CTL；然而，由于大多数患者在HLA - A区域位点是杂合的，因此必须了解主要的限制性等位基因，以便能够选择合适匹配的同种异体黑色素瘤。
