MHC class I bound to an immunodominant Theileria parva epitope demonstrates unconventional presentation to T cell receptors.
MHC class I bound to an immunodominant Theileria parva epitope demonstrates unconventional presentation to T cell receptors.
复制标题
DOI：
10.1371/journal.ppat.1001149
复制
发表时间：
2010-10-14
期刊：
影响因子：
6.7
通讯作者：
Ellis SA
中科院分区：
文献类型：
--
作者：
Macdonald IK;Harkiolaki M;Hunt L;Connelley T;Carroll AV;MacHugh ND;Graham SP;Jones EY;Morrison WI;Flower DR;Ellis SA
T细胞受体（TCR）对肽-MHC I类（pMHC）复合物的识别是针对病原体的适应性免疫应答中的关键事件。肽表位通常显示出强烈的优势等级，导致应答集中在有限数量的最优势表位上。这样的T细胞应答可能另外受到特定MHC等位基因优先于其他等位基因的限制。我们已经研究了这种知之甚少的现象，使用泰勒虫parva，原生动物寄生虫，导致往往致命的淋巴组织增生性疾病的牛。尽管其抗原的复杂性，由寄生虫感染诱导的CD 8 + T细胞反应显示出深刻的免疫优势，如由常见的和功能上重要的MHC I类等位基因N*01301呈递的Tp 1214 -224表位所示。我们提出了一个高分辨率的晶体结构的pMHC复合物，表明肽是在一个独特的提高构象。使用CD 8 + T细胞克隆的功能研究表明，这对TCR识别有显著影响。非常规结构是由MHC肽结合沟内的疏水脊产生的，在一组牛MHC等位基因中发现。在所有其他物种中非常罕见，这种特征在一小群小鼠MHC I类分子中可见。本分析中产生的数据有助于我们理解T细胞依赖性免疫应答的结构基础，提供了对决定高度免疫原性p-MHC复合物的因素的深入了解，因此可以在抗原表位预测和疫苗设计中具有价值。CD 8 + T细胞是宿主防御许多细胞内病原体所必需的。CD 8 + T细胞受体（TCR）检测感染细胞表面的小肽片段。这些肽表位由主要组织相容性复合体（MHC）分子结合。这种T细胞反应通常令人费解地集中在非常少的表位上，即使是对大型和复杂的病原体的反应。这些表位通常由特定的MHC分子呈递。这种现象被称为免疫优势。对免疫优势相关因素的深入了解将提高我们设计针对一系列传染性病原体的更有效疫苗的能力。我们的研究集中在一个经济上重要的原生动物寄生牛，泰勒虫parva。我们产生了与免疫显性T结合的MHC分子晶体。parva表位。晶体结构的分析表明，肽被保持在一个非常不寻常的构象，这是显着影响TCR识别，基于特定的CD 8 + T细胞克隆的研究。这些数据将有助于我们理解T细胞免疫的结构基础，并最终有助于疾病控制策略的发展。
T cell receptor (TCR) recognition of peptide-MHC class I (pMHC) complexes is a crucial event in the adaptive immune response to pathogens. Peptide epitopes often display a strong dominance hierarchy, resulting in focusing of the response on a limited number of the most dominant epitopes. Such T cell responses may be additionally restricted by particular MHC alleles in preference to others. We have studied this poorly understood phenomenon using Theileria parva, a protozoan parasite that causes an often fatal lymphoproliferative disease in cattle. Despite its antigenic complexity, CD8+ T cell responses induced by infection with the parasite show profound immunodominance, as exemplified by the Tp1214–224 epitope presented by the common and functionally important MHC class I allele N*01301. We present a high-resolution crystal structure of this pMHC complex, demonstrating that the peptide is presented in a distinctive raised conformation. Functional studies using CD8+ T cell clones show that this impacts significantly on TCR recognition. The unconventional structure is generated by a hydrophobic ridge within the MHC peptide binding groove, found in a set of cattle MHC alleles. Extremely rare in all other species, this feature is seen in a small group of mouse MHC class I molecules. The data generated in this analysis contribute to our understanding of the structural basis for T cell-dependent immune responses, providing insight into what determines a highly immunogenic p-MHC complex, and hence can be of value in prediction of antigenic epitopes and vaccine design. CD8+ T cells are essential for host defense to many intracellular pathogens. The CD8+ T cell receptor (TCR) detects small peptide fragments presented at the surface of infected cells. These peptide epitopes are bound by major histocompatibility complex (MHC) molecules. Such T cell responses are often inexplicably focused on a very small number of epitopes, even in response to large and complex pathogens. These epitopes are usually presented by specific MHC molecules. This phenomenon is known as immunodominance. An increased understanding of the factors involved in immunodominance would increase our ability to design more effective vaccines against a range of infectious pathogens. Our study focused on an economically important protozoan parasite of cattle, Theileria parva. We generated crystals of MHC molecules bound to an immunodominant T. parva epitope. Analysis of the crystal structure demonstrated that the peptide was held in a highly unusual conformation, which was shown to impact significantly on TCR recognition, based on studies of specific CD8+ T cell clones. These data will aid our understanding of the structural basis for T cell immunity and will ultimately contribute to development of disease control strategies.
登录
查看更多内容
DOI：
10.1186/1745-7580-3-2
发表时间：
2007-02-09
期刊：
Immunome research
影响因子：
--
作者：
Graham SP;Honda Y;Pellé R;Mwangi DM;Glew EJ;de Villiers EP;Shah T;Bishop R;van der Bruggen P;Nene V;Taracha EL
通讯作者：
Taracha EL
使用MPSS对原生动物Theileria parva的转录组分析表明，大多数基因在Schizont阶段具有转录活性。
影响因子：
14.9
作者：
Bishop, R;Shah, T;Pelle, R;Hoyle, D;Pearson, T;Haines, L;Brass, A;Hulme, H;Graham, SP;Taracha, ELN;Kanga, S;Lu, C;Hass, B;Wortman, J;White, O;Gardner, MJ;Nene, V;de Villiers, EP
通讯作者：
de Villiers, EP
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
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：
3.2
作者：
Birch, James;Murphy, Lisa;Ellis, Shirley A.
通讯作者：
Ellis, Shirley A.