PREFERENTIAL V-BETA-GENE USAGE AND LACK OF JUNCTIONAL SEQUENCE CONSERVATION AMONG HUMAN T-CELL RECEPTORS SPECIFIC FOR A TETANUS TOXIN DERIVED PEPTIDE - EVIDENCE FOR A DOMINANT ROLE OF A GERMLINE-ENCODED V-REGION IN ANTIGEN MAJOR HISTOCOMPATIBILITY COMPLEX RECOGNITION
PREFERENTIAL V-BETA-GENE USAGE AND LACK OF JUNCTIONAL SEQUENCE CONSERVATION AMONG HUMAN T-CELL RECEPTORS SPECIFIC FOR A TETANUS TOXIN DERIVED PEPTIDE - EVIDENCE FOR A DOMINANT ROLE OF A GERMLINE-ENCODED V-REGION IN ANTIGEN MAJOR HISTOCOMPATIBILITY COMPLEX RECOGNITION
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DOI：
10.1084/jem.175.3.765
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发表时间：
1992-03-01
影响因子：
15.3
通讯作者：
ACUTO, O
中科院分区：
文献类型：
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作者：
BOITEL, B;ERMONVAL, M;ACUTO, O
为了研究T细胞对人类中确定的肽/主要组织相容性（MHC）II类复合物的应答的结构和遗传基础，我们从不同HLA-DR单倍型的供体中建立了一个大的T细胞克隆组（61），并与破伤风毒素衍生肽（tt 830 -844）反应，该肽与大多数DR分子（通用肽）相关。通过使用基于细菌肠毒素的增殖测定和cDNA测序，我们发现在所研究的三个个体中优先使用特定的V β区基因片段V β 2.1（64%，n = 58），无论该肽是否由DR 6 wcI、DR 4 w 4或DRw11.1和DRw11.2等位基因呈递，这证明了共享的MHC II类抗原对于该肽特异性的T细胞受体（TCR）使用共享的V-β基因不是必需的。V-alpha基因的使用更加异质，至少有7个不同的V-alpha片段来自5个不同的家族，编码能够与V-beta-2.1链配对形成tt 830 -844/DR特异性结合位点的α链。有几个案例中发现的克隆局限于不同的DR等位基因，表达相同的V-β和（或非常密切相关的）V-α基因片段，不同的只是在他们的交界序列。因此，在某些情况下，TCR的推定互补决定区3（CDR 3）的变化可能改变MHC特异性并维持肽反应性。最后，与在其他定义的肽/MHC系统中观察到的相反，在α和β链的连接区发现了显著的异质性，即使对于具有相同的V-α和/或V-β基因片段和相同限制的TCR也是如此。在使用V-β-2.1-基因片段的14个抗tt 830 -844克隆中，发现14个独特的V-β-D-J-β-连接，在长度和/或氨基酸组成上没有明显的保守性。对于这种明显缺乏共同选择的特定连接序列的背景下，一个共同的V元素，V-β-2.1，一种解释是，这个V区起着主导作用，在识别的tt 830 -844/DR复合物。
To investigate the structural and genetic basis of the T cell response to defined peptide/major histocompatibility (MHC) class II complexes in humans, we established a large panel of T cell clones (61) from donors of different HLA-DR haplotypes and reactive with a tetanus toxin-derived peptide (tt830-844) recognized in association with most DR molecules (universal peptide). By using a bacterial enterotoxin-based proliferation assay and cDNA sequencing, we found preferential use of a particular V-beta-region gene segment, V-beta-2.1, in three of the individuals studied (64%, n = 58), irrespective of whether the peptide was presented by the DR6wcI, DR4w4, or DRw11.1 and DRw11.2 alleles, demonstrating that shared MHC class II antigens are not required for shared V-beta-gene use by T cell receptors (TCRs) specific for this peptide. V-alpha-gene use was more heterogeneous, with at least seven different V-alpha-segments derived from five distinct families encoding alpha-chains able to pair with V-beta-2.1 chains to form a tt830-844/DR-specific binding site. Several cases were found of clones restricted to different DR alleles that expressed identical V-beta and (or very closely related) V-alpha-gene segments and that differed only in their junctional sequences. Thus, changes in the putative complementary determining region 3 (CDR3) of the TCR may, in certain cases, alter MHC specificity and maintain peptide reactivity. Finally, in contrast to what has been observed in other defined peptide/MHC systems, a striking heterogeneity was found in the junctional regions of both alpha and beta-chains, even for TCRs with identical V-alpha and/or V-beta-gene segments and the same restriction. Among 14 anti-tt830-844 clones using the V-beta-2.1-gene segment, 14 unique V-beta-D-J-beta-junctions were found, with no evident conservation in length and/or amino acid composition. One interpretation for this apparent lack of coselection of specific junctional sequences in the context of a common V element, V-beta-2.1, is that this V region plays a dominant role in the recognition of the tt830-844/DR complex.