Potential role of HTLV-1 Tax-specific cytotoxic t lymphocytes expressing a unique t-cell receptor to promote inflammation of the central nervous system in myelopathy associated with HTLV-1.
Potential role of HTLV-1 Tax-specific cytotoxic t lymphocytes expressing a unique t-cell receptor to promote inflammation of the central nervous system in myelopathy associated with HTLV-1.
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DOI：
10.3389/fimmu.2022.993025
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发表时间：
2022
影响因子：
7.3
通讯作者：
Yamano, Yoshihisa
中科院分区：
文献类型：
--
作者：
Tanaka, Yukie;Sato, Tomoo;Yagishita, Naoko;Yamauchi, Junji;Araya, Natsumi;Aratani, Satoko;Takahashi, Katsunori;Kunitomo, Yasuo;Nagasaka, Misako;Kanda, Yoshinobu;Uchimaru, Kaoru;Morio, Tomohiro;Yamano, Yoshihisa
人类嗜T淋巴细胞病毒1（HTLV-1）感染导致两种严重的疾病：成人T细胞白血病/淋巴瘤（ATL）和HTLV-1相关性脊髓病（HAM）。免疫学研究显示，无症状携带者（AC）和ATL患者中的HTLV-1 Tax特异性CD 8+细胞毒性T细胞（Tax-CTL）在消除HTLV-1感染的宿主细胞中起重要作用，而HAM患者中的Tax-CTL触发针对浸润中枢神经系统（CNS）的HTLV-1感染的宿主细胞的过度免疫应答，导致局部炎症。我们之前对HTLV-1 Tax 301 -309（SFHSLHLLF）特异性Tax-CTL（Tax 301 -309-CTL）的评估显示，HLA-A*24：02+ AC和ATL患者共享一个独特的含有氨基酸（AA）序列基序PDR的T细胞受体（TCR），并通过对HTLV-1的强活性作为消除剂。然而，目前尚不清楚PDR+ Tax 301 -309-CTL是否也存在于HLA-A*24：02+ HAM患者中并参与HAM的发病机制。在本研究中，我们通过高通量TCR库分析技术，我们发现HLA-A*24：02+ HAM患者外周血（PB）中Tax 301 -309-CTL的TCR库是偏斜的，并且在HAM患者中具有独特的TCR基序PDR（10/11例）。其余病例主要表达（-DR、P-R和PD-），与PDR相差一个AA。总体而言，具有独特AA序列基序PDR或（-DR、P-R和PD-）的TCR占HLA-A*24：02+ HAM患者的Tax 301 -309-CTL库的总计0.3-98.1%。此外，来自4名HAM患者的脑脊液（CSF）中T细胞的TCR库分析证明PDR+ Tax 301 -309-CTL和TCR-CTL可能与HAM患者的免疫应答有关。（-DR、P-R和PD-）+Tax 301 -309-CTL在HAM患者的CSF中有效迁移和积累，促进炎症增加，尽管我们观察到PB中它们的频率与CSF新蝶呤（HAM的已知疾病活动生物标志物）的水平之间没有明显的显著相关性。此外，为了更好地了解PDR+ Tax 301 -309-CTL的潜在功能，我们通过Tax 301 -309-CTL的单细胞RNA测序进行了免疫谱分析，结果显示PDR+ Tax 301 -309-CTL上调了自然杀伤细胞标志物KLRB 1（CD 161）的基因表达，这可能与T细胞活化和记忆T细胞的高细胞毒性潜力有关。这些发现表明，独特和共享的PDR+ Tax 301 -309-CTL在促进HAM患者CNS内的局部炎症中具有潜在作用。
Human T-lymphotropic virus 1 (HTLV-1) infection causes two serious diseases: adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy (HAM). Immunological studies have revealed that HTLV-1 Tax-specific CD8+ cytotoxic T-cells (Tax-CTLs) in asymptomatic carriers (ACs) and ATL patients play an important role in the elimination of HTLV-1-infected host cells, whereas Tax-CTLs in HAM patients trigger an excessive immune response against HTLV-1-infected host cells infiltrating the central nervous system (CNS), leading to local inflammation. Our previous evaluation of HTLV-1 Tax301-309 (SFHSLHLLF)-specific Tax-CTLs (Tax301-309-CTLs) revealed that a unique T-cell receptor (TCR) containing amino acid (AA)-sequence motif PDR, was shared among HLA-A*24:02+ ACs and ATL patients and behaved as an eliminator by strong activity against HTLV-1. However, it remains unclear whether PDR+Tax301-309-CTLs also exist in HLA-A*24:02+ HAM patients and are involved in the pathogenesis of HAM. In the present study, by high-throughput TCR repertoire analysis technology, we revealed TCR repertoires of Tax301-309-CTLs in peripheral blood (PB) of HLA-A*24:02+ HAM patients were skewed, and a unique TCR-motif PDR was conserved in HAM patients (10 of 11 cases). The remaining case dominantly expressed (-DR, P-R, and PD-), which differed by one AA from PDR. Overall, TCRs with unique AA-sequence motifs PDR, or (-DR, P-R, and PD-) accounted for a total of 0.3-98.1% of Tax301-309-CTLs repertoires of HLA-A*24:02+ HAM patients. Moreover, TCR repertoire analysis of T-cells in the cerebrospinal fluid (CSF) from four HAM patients demonstrated the possibility that PDR+Tax301-309-CTLs and (-DR, P-R, and PD-)+Tax301-309-CTLs efficiently migrated and accumulated in the CSF of HAM patients fostering increased inflammation, although we observed no clear significant correlation between the frequencies of them in PB and the levels of CSF neopterin, a known disease activity biomarker of HAM. Furthermore, to better understand the potential function of PDR+Tax301-309-CTLs, we performed immune profiling by single-cell RNA-sequencing of Tax301-309-CTLs, and the result showed that PDR+Tax301-309-CTLs up-regulated the gene expression of natural killer cell marker KLRB1 (CD161), which may be associated with T-cell activation and highly cytotoxic potential of memory T-cells. These findings indicated that unique and shared PDR+Tax301-309-CTLs have a potential role in promoting local inflammation within the CNS of HAM patients.
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影响因子：
8
作者：
Fergusson JR;Hühn MH;Swadling L;Walker LJ;Kurioka A;Llibre A;Bertoletti A;Holländer G;Newell EW;Davis MM;Sverremark-Ekström E;Powrie F;Capone S;Folgori A;Barnes E;Willberg CB;Ussher JE;Klenerman P
通讯作者：
Klenerman P
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP
影响因子：
82.9
作者：
Gattinoni L;Speiser DE;Lichterfeld M;Bonini C
通讯作者：
Bonini C
影响因子：
5.4
作者：
Bourcier, KD;Lim, DG;Hafler, DA
通讯作者：
Hafler, DA
影响因子：
5.3
作者：
Enose-Akahata, Yoshimi;Oh, Unsong;Jacobson, Steven
通讯作者：
Jacobson, Steven