Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
Int J Mol Sci. 2021 Feb 28;22(5):2428. doi: 10.3390/ijms22052428.
Nickel (Ni) is one of the most common allergens, affecting around 10-15% of the general population. As the demand for orthopedic implant surgery rises, the number of surgical revisions due to joint implant failure also increases. There is evidence that some patients develop joint failure due to an immune response to a component of the implant, and we have found that Ni is an especially important cause. Hence, understanding the mechanisms by which Ni allergy induces joint implant failure becomes a critical research question. The structural basis of Ni activation of pathogenic T cells is still not clear. The purpose of this study was to characterize Ni-reactive T cell repertoires derived from the peripheral blood of joint failure patients due to Ni sensitization using single-cell sequencing techniques. We stimulated the proliferation of Ni -reactive T cells from two implant failure patients in vitro, and sorted them for single-cell VDJ sequencing (10× genomics). We identified 2650 productive V-J spanning pairs. Both TCR α chains and β chains were enriched. TRBV18 usage is the highest in the P7 CD4+ population (18.1%), and TRBV5-1 usage is the highest in the P7 CD8+ population (12.1%). TRBV19 and TRBV20-1 segments are present in a high percentage of both P7 and P9 sequenced T cells. Remarkably, the alpha and beta chain combination of TRAV41-TRBV18 accounts for 13.5% of the CD4+ population of P7 patient. Compared to current Ni specific T cell repertoire studies of contact dermatitis, the Vα and Vβ usages of these joint implant failure patients were different. This could be due to the different availability of self-peptides in these two different tissues. However, TRBV19 (Vβ17) was among frequently used TCR β chains, which are common in previous reports. This implies that some pathogenic T cells could be similar in Ni hypersensitivities in skin and joints. The alignment of the TCR CDR3β sequences showed a conserved glutamic acid (Glu) that could potentially interact with Ni. The study of these Ni specific TCRs may shed light on the molecular mechanism of T cell activation by low molecular weight chemical haptens.
镍（Ni）是最常见的过敏原之一，影响大约 10-15%的普通人群。随着骨科植入物手术需求的增加，由于关节植入物失效而进行的手术翻修数量也在增加。有证据表明，一些患者由于对植入物的一个成分产生免疫反应而导致关节失效，我们发现镍是一个特别重要的原因。因此，了解镍过敏如何导致关节植入物失效的机制成为一个关键的研究问题。镍激活致病 T 细胞的结构基础仍不清楚。本研究旨在使用单细胞测序技术，从因镍致敏而导致关节失效的患者外周血中鉴定镍反应性 T 细胞的特征。我们体外刺激了两名植入物失效患者的镍反应性 T 细胞增殖，并对其进行了单细胞 VDJ 测序（10x 基因组学）。我们鉴定了 2650 个有功能的 V-J 跨越对。同时富集了 TCR α 链和β 链。P7 CD4+群体中 TRBV18 的使用率最高（18.1%），而 P7 CD8+群体中 TRBV5-1 的使用率最高（12.1%）。TRBV19 和 TRBV20-1 片段在 P7 和 P9 测序的 T 细胞中均以高比例存在。值得注意的是，TRAV41-TRBV18 的 alpha 和 beta 链组合占 P7 患者 CD4+群体的 13.5%。与目前接触性皮炎的镍特异性 T 细胞库研究相比，这些关节植入物失效患者的 Vα 和 Vβ 使用情况不同。这可能是由于这两种不同组织中自身肽的可用性不同。然而，TRBV19（Vβ17）是经常使用的 TCRβ 链之一，这在以前的报告中很常见。这意味着在皮肤和关节中的镍超敏反应中，一些致病性 T 细胞可能相似。TCR CDR3β 序列的比对显示了一个保守的谷氨酸（Glu），它可能与 Ni 相互作用。对这些镍特异性 TCR 的研究可能有助于阐明低分子量化学半抗原激活 T 细胞的分子机制。
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