Bettinotti M P, Kim C J, Lee K H, Roden M, Cormier J N, Panelli M, Parker K K, Marincola F M
HLA Laboratory, Department of Transfusion Medicine, Clinical Center, Bethesda, MD 20892, USA.
J Immunol. 1998 Jul 15;161(2):877-89.
The exclusiveness of the relationship between peptide and HLA alleles, combined with their extensive polymorphism, emphasizes the need for immunization strategies based on endogenous processing of full length proteins (containing multiple epitopic determinants) for presentation to T cells. This could allow vaccination regardless of the patient's HLA phenotype, assuming that individual molecules can be efficient T cell Ags in association with various HLA alleles. An endogenous system of Ag presentation was developed using dendritic cells infected with recombinant viral vectors expressing the melanoma-associated Ag MART-1/Melan A. CD8+ T cells from melanoma patients were activated in vitro by coincubation with infected dendritic cells and tested for recognition of HLA-A-matched melanoma targets. This allowed the analysis of T cell induction in association with any HLA-A allele of a given patient's phenotype. In this system, MART-1/Melan A could not efficiently immunize in association with HLA-A alleles other than A0201, including the one residue variant from A0201: HLA-A0226. Clonal analysis of MART-1/Melan A-specific CTL confirmed that MART-1/Melan A immunodominance is strongly restricted to the AAGIGILTV/HLA-A0201 combination. The stringent epitope/allele requirements for MART-1/Melan A/TCR interactions were not associated with limitations in the TCR repertoire. In conclusion, autologous induction of MART-1/Melan A CTL by whole Ag processing and presentation is restricted to a unique allele/ligand combination and is excluded by minimal changes in HLA structure. Thus, whole protein vaccination for small m.w. Ags may provide no further advantage over a peptide-based approach.
肽与HLA等位基因之间关系的排他性，再加上它们广泛的多态性，凸显了基于全长蛋白质（包含多个表位决定簇）的内源性加工以呈递给T细胞的免疫策略的必要性。假设单个分子与各种HLA等位基因结合时可以成为有效的T细胞抗原，那么这将允许无论患者的HLA表型如何都能进行疫苗接种。利用感染了表达黑色素瘤相关抗原MART-1/黑色素A的重组病毒载体的树突状细胞，开发了一种内源性抗原呈递系统。黑色素瘤患者的CD8 + T细胞通过与感染的树突状细胞共同孵育在体外被激活，并测试其对HLA-A匹配的黑色素瘤靶标的识别能力。这使得能够分析与给定患者表型的任何HLA-A等位基因相关的T细胞诱导情况。在这个系统中，除了A0201之外，MART-1/黑色素A与其他HLA-A等位基因结合时不能有效地进行免疫，包括来自A0201的一个残基变体：HLA-A0226。对MART-1/黑色素A特异性CTL的克隆分析证实，MART-1/黑色素A免疫优势强烈局限于AAGIGILTV/HLA-A0201组合。MART-1/黑色素A/TCR相互作用严格的表位/等位基因要求与TCR库的限制无关。总之，通过全抗原加工和呈递进行MART-1/黑色素A CTL的自体诱导仅限于独特的等位基因/配体组合，并且会因HLA结构的微小变化而被排除。因此，对于小分子抗原的全蛋白疫苗接种可能不会比基于肽的方法提供更多优势。
