Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen
Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen
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DOI：
10.4049/jimmunol.180.3.1526
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发表时间：
2008-02-01
影响因子：
4.4
通讯作者：
Fong, Lawrence
中科院分区：
文献类型：
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作者：
Hou, Yafei;Kavanagh, Brian;Fong, Lawrence
异源多肽被用来增强肿瘤相关AGS的免疫原性，以打破T细胞对这些自身蛋白的耐受。其中一种改变的多肽配体(Cap1-6D)来自人类癌胚抗原CEA(605-613)(Cap1)的表位。在接受由这种改变的多肽组成的肿瘤疫苗的结肠癌患者中已经看到了临床反应。目前尚不清楚Cap1-6D是作为Cap1特异性T细胞的T细胞激动剂还是诱导不同的T细胞。因此，我们研究了Cap1-6D和Cap1诱导的T细胞谱系。用Cap1-6D多肽(6D-CTL)或Cap1多肽(Cap1-CTL)构建人CTL细胞系和克隆。对平行诱导的T细胞针对这些靶肽的TCRVβ使用率和功能亲和力进行了评估。激动剂Cap1-6D诱导的主要CTL谱系仅限于CDR3长度均一的TCR Vβ1-J2。相反，大多数Cap1-CTL使用不同的Vβ1基因，也具有不同的CDR3长度。与Cap1-CTL相比，6D-CTL对Cap1-6D多肽具有较高的亲和力，但对天然Cap1多肽的亲和力较低。尽管如此，6D-CTL仍能裂解具有天然表位的靶点。与这些功能结果一致的是，6D-CTL具有与Cap-1肽/MHC四聚体结合的TCR，结合强度高于Cap1-CTL，但通过四聚体衰变测定，与肽/MHC形成的相互作用不那么稳定。这些结果表明，CEA修饰的多肽配体可以诱导不同功能的癌胚抗原反应性T细胞。
Heteroclitic peptides are used to enhance the immunogenicity of tumor-associated Ags to break T cell tolerance to these self-proteins. One such altered peptide ligand (Cap1-6D) has been derived from an epitope in human carcinoembryonic Ag, CEA(605-613) (Cap1). Clinical responses have been seen in colon cancer patients receiving a tumor vaccine comprised of this altered peptide. Whether Cap1-6D serves as a T cell agonist for Cap1-specific T cells or induces different T cells is unknown. We, therefore, examined the T cell repertoires elicited by Cap1-6D and Capl. Human CTL lines and clones were generated with either Cap1-6D peptide (6D-CTLs) or Cap1 peptide (Cap1-CTLs). The TCR V beta usage and functional avidity of the T cells induced in parallel against these target peptides were assessed. The predominant CTL repertoire induced by agonist Cap1-6D is limited to TCR V beta 1-J2 with homogenous CDR3 lengths. In contrast, the majority of Cap1-CTLs use different V beta 1 genes and also had diverse CDR3 lengths. 6D-CTLs produce IFN-gamma in response to Cap1-6D peptide with high avidity, but respond with lower avidity to the native Capl peptide when compared with the Cap1-CTLs. Nevertheless, 6D-CTLs could still lyse targets bearing the native epitope. Consistent with these functional results, 6D-CTLs possess TCRs that bind Cap-1 peptide/MHC tetramer with higher intensity than Cap1-CTLs but form less stable interactions with peptide/MHC as measured by tetramer decay. These results demonstrate that priming with this CEA-derived altered peptide ligand can induce distinct carcinoembryonic Ag-reactive T cells with different functional capacities.