Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses.
Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses.
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DOI：
10.1084/jem.179.6.1933
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发表时间：
1994-06-01
期刊：
影响因子：
--
通讯作者：
Welsh RM
中科院分区：
文献类型：
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作者：
Selin LK;Nahill SR;Welsh RM
对不同病毒和病毒蛋白之间关系的分析主要集中在线性氨基酸序列之间的同源性，但T细胞识别水平的交叉反应可能不依赖于几个氨基酸的保守线性序列。先前用淋巴细胞性脉络膜脑膜炎病毒（LCMV）免疫的 C57BL/6 小鼠对皮钦德病毒（PV）和牛痘病毒（VV）的 CTL 反应包括对 LCMV 特异性的记忆细胞毒性 T 淋巴细胞（CTL）的重新激活。有限稀释测定 (LDA) 表明，LCMV 免疫小鼠中记忆细胞的重新激活至少部分与克隆水平的交叉反应有关，尽管非免疫小鼠中这些病毒的急性感染引发了 CTL 反应，而在传统的批量 CTL 测定中不会发生交叉反应。当仅用第二种病毒而不是未感染的腹膜渗出细胞 (PEC) 体外刺激时，急性感染 PV 或 VV 的 LCMV 免疫小鼠的脾白细胞中会产生 LCMV 的前体 CTL (pCTL)。由PV感染激活的LCMV特异性CTL克隆介导的细胞毒性被抗CD8抗体极大地抑制，这表明这些识别LCMV感染靶标的记忆CTL克隆的亲和力较低。用 PV 或 VV 体外刺激的 LCMV 免疫脾细胞表现出对异源病毒的低但显着的前体频率 (p/f)，并且当体外针对 LCMV 刺激时，来自 PV 或 VV 免疫小鼠的脾细胞对 LCMV 产生低但显着的 p/f。 LCMV 和 PV 之间交叉反应的短期 CTL 克隆源自急性感染 PV 的 LCMV 免疫小鼠的脾白细胞。为了区分交叉反应是针对病毒肽还是针对病毒诱导的内源性细胞新抗原，我们证明，用免疫显性 LCMV NP 肽刺激的 LCMV 免疫脾白细胞可以产生 pCTL 频率，PV 频率约为 LCMV 频率的 1/4-1/7。从与 LCMV NP 肽等效位点产生的部分同源 PV 肽不会使靶标对 LCMV 或 PV 特异性 CTL 的裂解敏感，这表明杀伤中的交叉反应性不是由于进化上保守的等效序列所致。实验还表明，先前对一种病毒的免疫力可以调节未来对第二种病毒的初级免疫反应。 LCMV 免疫小鼠急性 PV 感染后，PV 的 pCTL 频率升高，PV 和 VV 免疫小鼠急性 LCMV 感染后，LCMV 的 pCTL 频率升高。（摘要截断为 400 字）
Analyses of the relationships between different viruses and viral proteins have focused on homologies between linear amino acid sequences, but cross-reactivities at the level of T cell recognition may not be dependent on a conserved linear sequence of several amino acids. The CTL response to Pichinde virus (PV) and vaccinia virus (VV) in C57BL/6 mice previously immunized with lymphocytic choriomeningitis virus (LCMV) included the reactivation of memory cytotoxic T lymphocyte (CTL) specific to LCMV. Limiting dilution assays (LDA) demonstrated that at least part of this reactivation of memory cells in LCMV-immune mice related to cross-reactivity at the clonal level, even though acute infections with these viruses in nonimmune mice elicited CTL responses that did not cross-react in conventional bulk CTL assays. Precursor CTL (pCTL) to LCMV were generated in splenic leukocytes from LCMV-immune mice acutely infected with PV or VV when stimulated in vitro with only the second virus but not with uninfected peritoneal exudate cells (PECs). Cytotoxicity mediated by LCMV-specific CTL clones activated by PV infection was greatly inhibited by anti-CD8 antibody, suggesting that these memory CTL clones recognizing LCMV-infected targets were of low affinity. LCMV-immune splenocytes stimulated in vitro with PV or VV demonstrated a low but significant precursor frequency (p/f) to the heterologous viruses, and splenocytes from PV- or VV-immune mice when stimulated in vitro against LCMV generated a low but significant p/f to LCMV. Short-term CTL clones cross-reactive between LCMV and PV were derived from splenic leukocytes from LCMV-immune mice acutely infected with PV. To distinguish whether the cross-reactivity was directed against a viral peptide or a virus-induced endogenous cellular neoantigen, we demonstrated that a pCTL frequency to PV about 1/4-1/7 that of the frequency to LCMV could be generated from LCMV-immune splenic leukocytes stimulated with the immunodominant LCMV NP peptide. A partially homologous PV peptide generated from the equivalent site to the LCMV NP peptide did not sensitize targets to lysis by either LCMV- or PV-specific CTLs, suggesting that the cross-reactivity in killing was not due to evolutionarily conserved equivalent sequences. Experiments also indicated that prior immunity to one virus could modulate future primary immune responses to a second virus. Elevated pCTL frequencies to PV were seen after acute PV infection of LCMV- immune mice, and elevated pCTL frequencies to LCMV were seen after acute LCMV infection of PV- and VV-immune mice.(ABSTRACT TRUNCATED AT 400 WORDS)