The T cell repertoire for recognition of a phylogenetically distant protein antigen. Peptide specificity and MHC restriction of staphylococcal nuclease-specific T cell clones.
The T cell repertoire for recognition of a phylogenetically distant protein antigen. Peptide specificity and MHC restriction of staphylococcal nuclease-specific T cell clones.
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DOI：
10.1084/jem.164.3.897
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发表时间：
1986-09-01
期刊：
影响因子：
--
通讯作者：
Hodes RJ
中科院分区：
文献类型：
--
作者：
Finnegan A;Smith MA;Smith JA;Berzofsky J;Sachs DH;Hodes RJ
先前的研究（1）已经表明，对潜在的复杂蛋白抗原特异的鼠T细胞库实际上对与给定Ia分子相关的抗原上的有限数量的抗原表位特异。由于这些研究通常分析对抗原的反应，这些抗原与同源小鼠分子仅在几个氨基酸上不同，因此对自身蛋白的耐受性可能是导致在对密切相关蛋白的反应中观察到的有限T细胞库的原因。因此，确定T细胞对结构上和遗传学上更远的蛋白质分子的识别是否也会对该分子上有限数量的免疫显性肽显示特异性是有意义的。本实验旨在研究细菌源性抗原葡萄球菌核酸酶（Nase）特异性T细胞克隆的抗原精细特异性和MHC限制性。在（H-2b X H-2a）F1（B6 AF 1）T细胞中产生的T细胞克隆显示对Nase具有特异性，并且受到Ab α Ab β或Ek α Ek β的限制。然后使用溴化氰和胰蛋白酶片段以及一系列对应于并跨越Nase分子的整个序列的重叠的20-氨基酸合成肽来分析这些克隆的精细特异性。两个Ab α Ab β-限制性克隆对肽91-110高度响应，而对其它合成Nase肽不响应。相反，七个Ek α Ek β-限制性克隆对肽81-100有一致的应答，而对91-110或其它Nase肽无应答.这些Ek α Ek β限制性T细胞中的某些表达了有趣的交叉反应性，因为它们对肽51-70以及81-100有反应，尽管对51-70的反应的特征在于显著移动的剂量-反应曲线，表明该肽的活化效率降低。对这些区域的氨基酸序列的分析表明，这种意想不到的交叉反应可能具有结构基础。与所研究的任何B6 AF 1克隆相反，从BALB/c T细胞产生的单个Nase特异性T细胞系仅对肽61-80应答，而不对其他肽（包括81-100或91-110）应答。总的来说，这些发现表明Nase特异性T细胞对离散的Nase肽有反应。此外，目前的研究结果表明，在复杂的和高度外来的蛋白抗原的T细胞识别中，有限数量的肽表位优先被与给定的Ia分子相关的T细胞识别。
Previous studies (1) have indicated that the repertoire of murine T cells specific for a potentially complex protein antigen is in fact specific for a limited number of antigenic epitopes on that antigen in association with a given Ia molecule. Since those studies generally analyzed responses to antigens that differ in only a few amino acids from homologous murine molecules, it was possible that tolerance to self proteins was responsible for the limited T cell repertoire seen in responses to closely related proteins. It was therefore of interest to determine whether T cell recognition of a structurally and phylogenetically more distant protein molecule would also show specificity for a limited number of immunodominant peptides on that molecule. A series of experiments was designed to study the antigen fine specificity and MHC restriction of T cell clones specific for the bacterially derived antigen staphylococcal nuclease (Nase). T cell clones generated in (H-2b X H-2a)F1 (B6AF1) T cells were shown to be specific for Nase and to be restricted by either Ab alpha Ab beta or Ek alpha Ek beta. The fine specificity of these clones was then analyzed using cyanogen bromide and tryptic fragments and a series of overlapping 20-amino-acid synthetic peptides corresponding to and spanning the entire sequence of the Nase molecule. Two Ab alpha Ab beta- restricted clones were highly responsive to peptide 91-110, and not to other synthetic Nase peptides. In contrast, seven Ek alpha Ek beta- restricted clones were consistently responsive to peptide 81-100 and not to 91-110 or to other Nase peptides. Certain of these Ek alpha Ek beta-restricted T cells expressed an interesting crossreactivity, in that they responded to peptide 51-70 as well as to 81-100, although the response to 51-70 was characterized by a markedly shifted dose-response curve, indicating a reduced efficiency of activation by this peptide. Analysis of the amino acid sequences of these regions indicates that this unexpected crossreaction may have a structural basis. A single Nase-specific T cell line generated from BALB/c T cells was, in contrast to any of the B6AF1 clones studied, responsive only to peptide 61-80 and not to other peptides, including 81-100 or 91-110. Collectively, these findings show that Nase-specific T cells are responsive to discrete Nase peptides. Moreover, the present findings suggest that in T cell recognition of a complex and highly foreign protein antigen, a limited number of peptide epitopes are preferentially recognized by T cells in association with a given Ia molecule.