CD8 T-cell responses against the immunodominant Theileria parva peptide Tp249-59 are composed of two distinct populations specific for overlapping 11-mer and 10-mer epitopes.
CD8 T-cell responses against the immunodominant Theileria parva peptide Tp249-59 are composed of two distinct populations specific for overlapping 11-mer and 10-mer epitopes.
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DOI：
10.1111/imm.12637
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发表时间：
2016-10
期刊：
影响因子：
6.4
通讯作者：
Morrison WI
中科院分区：
文献类型：
--
作者：
Connelley TK;Li X;MacHugh N;Colau D;Graham SP;van der Bruggen P;Taracha EL;Gill A;Morrison WI
对微小泰勒氏菌的免疫与CD8T细胞反应有关，CD8T细胞反应表现出免疫优势，集中在有限数量的表位上。作为疫苗的候选者，针对免疫优势表位的反应的表征是新型疫苗开发的关键组成部分。我们先前已经证明，Tp249-59和Tp1214-224表位分别在Bola-A10和Bola-18 MHC I纯合子动物中主导CD8 T细胞反应。在这项研究中，这些表位的多肽-MHC I四聚体和一个次要的BOLA-A10限制性表位(Tp298-106)被用来促进对表位特异性CD8T细胞的准确和快速的计数。在验证这些四聚体的过程中，相当大比例的Tp249-59反应性T细胞未能与四聚体结合，这表明这个群体与已知的表位是不同的。我们证明Tp250-59代表一个不同的表位，用Tp50-59和Tp49-59产生的四聚体没有交叉反应。Tp249-59和Tp250-59表位使用不同的丝氨酸残基作为N端锚，与呈现的MHC I分子结合。分子动力学模拟预测这两个肽-MHC I复合体采用不同的结构构象，T细胞受体β序列分析表明，Tp249-59和Tp250-59被非重叠的T细胞受体识别。总而言之，这些数据表明，尽管只有一个残基的差异，但Tp249-59和Tp250-59表位形成了不同的T细胞受体识别配体。四聚体分析证实了Tp1214-224在BOLA-A18动物中的免疫优势，在BOLA-A10动物中，Tp249-59表位反应一般比Tp250-59反应更占优势，并证实Tp298-106反应是次要的。
Immunity against Theileria parva is associated with CD8 T‐cell responses that exhibit immunodominance, focusing the response against limited numbers of epitopes. As candidates for inclusion in vaccines, characterization of responses against immunodominant epitopes is a key component in novel vaccine development. We have previously demonstrated that the Tp249–59 and Tp1214–224 epitopes dominate CD8 T‐cell responses in BoLA‐A10 and BoLA‐18 MHC I homozygous animals, respectively. In this study, peptide–MHC I tetramers for these epitopes, and a subdominant BoLA‐A10‐restricted epitope (Tp298–106), were generated to facilitate accurate and rapid enumeration of epitope‐specific CD8 T cells. During validation of these tetramers a substantial proportion of Tp249–59‐reactive T cells failed to bind the tetramer, suggesting that this population was heterogeneous with respect to the recognized epitope. We demonstrate that Tp250–59 represents a distinct epitope and that tetramers produced with Tp50–59 and Tp49–59 show no cross‐reactivity. The Tp249–59 and Tp250–59 epitopes use different serine residues as the N‐terminal anchor for binding to the presenting MHC I molecule. Molecular dynamic modelling predicts that the two peptide–MHC I complexes adopt structurally different conformations and Tcell receptor β sequence analysis showed that Tp249–59 and Tp250–59 are recognized by non‐overlapping T‐cell receptor repertoires. Together these data demonstrate that although differing by only a single residue, Tp249–59 and Tp250–59 epitopes form distinct ligands for T‐cell receptor recognition. Tetramer analysis of T. parva‐specific CD8 T‐cell lines confirmed the immunodominance of Tp1214–224 in BoLA‐A18 animals and showed in BoLA‐A10 animals that the Tp249–59 epitope response was generally more dominant than the Tp250–59 response and confirmed that the Tp298–106 response was subdominant.
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影响因子：
4.4
作者：
Connelley T;Aerts J;Law A;Morrison WI
通讯作者：
Morrison WI
影响因子：
6.7
作者：
Macdonald IK;Harkiolaki M;Hunt L;Connelley T;Carroll AV;MacHugh ND;Graham SP;Jones EY;Morrison WI;Flower DR;Ellis SA
通讯作者：
Ellis SA
影响因子：
4.4
作者：
Derre, Laurent;Ferber, Mathias;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
3.1
作者：
Graham, Simon P.;Pelle, Roger;Taracha, Evans L. N.
通讯作者：
Taracha, Evans L. N.
影响因子：
56.9
作者：
Altman, JD;Moss, PAH;Davis, MM
通讯作者：
Davis, MM