gp100/pmel 17 is a murine tumor rejection antigen: induction of "self"-reactive, tumoricidal T cells using high-affinity, altered peptide ligand.
gp100/pmel 17 is a murine tumor rejection antigen: induction of "self"-reactive, tumoricidal T cells using high-affinity, altered peptide ligand.
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GP100/PMEL 17是一种鼠肿瘤排斥抗原：使用高亲和力，改变肽配体改变的“自我”反应性，肿瘤T细胞。
DOI：
10.1084/jem.188.2.277
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发表时间：
1998-07-20
期刊：
影响因子：
--
通讯作者：
Restifo NP
中科院分区：
文献类型：
--
作者：
Overwijk WW;Tsung A;Irvine KR;Parkhurst MR;Goletz TJ;Tsung K;Carroll MW;Liu C;Moss B;Rosenberg SA;Restifo NP
许多肿瘤相关抗原是非突变的、免疫原性差的组织分化抗原。它们的弱免疫原性可能是由于“自身”耐受。为了诱导自身反应性T细胞，我们研究了对gp 100/pmel 17的免疫应答，gp 100/pmel 17是由正常黑素细胞和黑色素瘤细胞天然表达的抗原。虽然编码gp 100的小鼠同源物的重组牛痘病毒（rVV）是非免疫原性的，但用编码人gp 100的rVV免疫正常C57 BL/6小鼠引起特异性CD 8 + T细胞应答。这些淋巴细胞在体外与mgp 100交叉反应，并在过继转移后治疗建立的B16黑素瘤。为了理解人类版本gp 100的更大免疫原性的机制，我们表征了被T细胞识别的由H-2Db限制的9-氨基酸（AA）表位。诱导特异性T细胞与人，但不是小鼠gp 100的能力导致的主要组织相容性复合体（MHC）的I类限制性表位内的差异，而不是从其他地方的分子中的差异，证明了实验中，小鼠免疫rVV含有编码这些表位的小基因。尽管人（hgp 10025 -33）和小鼠（mgp 10025 -33）表位同源，但三种NH 2末端AA的差异导致人肽稳定RMA-S细胞上“空”Db的能力增加2个对数，触发T细胞释放干扰素γ的能力增加3个对数。因此，偶然存在的肽同源物具有显着更大的亲和力的MHC I类导致产生自身反应性T细胞。高亲和力，改变的肽配体可能是有用的，在合理设计的重组和合成疫苗，靶向组织分化抗原表达的肿瘤。
Many tumor-associated antigens are nonmutated, poorly immunogenic tissue differentiation antigens. Their weak immunogenicity may be due to “self”-tolerance. To induce autoreactive T cells, we studied immune responses to gp100/pmel 17, an antigen naturally expressed by both normal melanocytes and melanoma cells. Although a recombinant vaccinia virus (rVV) encoding the mouse homologue of gp100 was nonimmunogenic, immunization of normal C57BL/6 mice with the rVV encoding the human gp100 elicited a specific CD8+ T cell response. These lymphocytes were cross-reactive with mgp100 in vitro and treated established B16 melanoma upon adoptive transfer. To understand the mechanism of the greater immunogenicity of the human version of gp100, we characterized a 9-amino acid (AA) epitope, restricted by H-2Db, that was recognized by the T cells. The ability to induce specific T cells with human but not mouse gp100 resulted from differences within the major histocompatibility complex (MHC) class I–restricted epitope and not from differences elsewhere in the molecule, as was evidenced by experiments in which mice were immunized with rVV containing minigenes encoding these epitopes. Although the human (hgp10025–33) and mouse (mgp10025–33) epitopes were homologous, differences in the three NH2-terminal AAs resulted in a 2-log increase in the ability of the human peptide to stabilize “empty” Db on RMA-S cells and a 3-log increase in its ability to trigger interferon γ release by T cells. Thus, the fortuitous existence of a peptide homologue with significantly greater avidity for MHC class I resulted in the generation of self-reactive T cells. High-affinity, altered peptide ligands might be useful in the rational design of recombinant and synthetic vaccines that target tissue differentiation antigens expressed by tumors.