Infection of adult thymus with murine retrovirus induces virus-specific central tolerance that prevents functional memory CD8+ T cell differentiation.
Infection of adult thymus with murine retrovirus induces virus-specific central tolerance that prevents functional memory CD8+ T cell differentiation.
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DOI：
10.1371/journal.ppat.1003937
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Miyazawa M
中科院分区：
文献类型：
--
作者：
Takamura S;Kajiwara E;Tsuji-Kawahara S;Masumoto T;Fujisawa M;Kato M;Chikaishi T;Kawasaki Y;Kinoshita S;Itoi M;Sakaguchi N;Miyazawa M
在慢性病毒感染中，持续的抗原呈递导致病毒特异性CD8+ T细胞的进行性耗竭。然而，已经清楚的是，从胸腺新产生的病毒特异性幼稚CD8+ T细胞可以用持续抗原引发。在低抗原密度和消退的炎症的情况下，新致敏的CD8+ T细胞优先被募集到功能记忆库中。因此，从胸腺持续募集幼稚CD8+ T细胞对于在慢性感染动物中保存功能性记忆CD8+ T细胞群体是重要的。Friend病毒（FV）是在成年小鼠中建立慢性感染的致病性鼠逆转录病毒，其通过在感染的早期阶段诱导的病毒特异性CD8+ T细胞的深度耗竭而得到支持。在这里，我们展示了一个额外的逃避策略，其中FV有效地传播到胸腺，最终导致克隆删除的胸腺细胞是反应的FV抗原。由于所导致的病毒特异性近期胸腺移出物的缺乏，沿着上述抗原经历的外周CD8+ T细胞的耗尽，用FV慢性感染的小鼠不能建立功能性病毒特异性CD8+ T细胞库，并且对表达FV编码的抗原的肿瘤细胞的攻击高度敏感。然而，在未感染的小鼠中产生的FV特异性幼稚CD8+ T细胞可以在转移到慢性感染的动物中时被致敏并分化为功能性记忆CD8+ T细胞。这些发现表明，病毒诱导的中枢耐受性在感染的慢性阶段发展，加速了功能失调的记忆性CD8+ T细胞的积累。在胸腺细胞发育过程中，识别自身抗原的细胞被称为负选择的过程特异性地删除。然而，一些病原体传播到胸腺，并且可以在该器官内诱导外源抗原呈递，导致病原体特异性T淋巴细胞前体的潜在有害克隆缺失。在慢性感染中，由于持续抗原的持续刺激，外周中的病原体特异性T细胞逐渐失去其功能，这种现象称为T细胞耗竭。然而，在感染的慢性期新鲜引发的病原体反应性幼稚T细胞仍然可以补充记忆T细胞的功能池。因此，在外周衰竭的情况下缺乏它们的产生可能最终导致功能性记忆T细胞的丧失以及由此导致的病原体控制的缺乏。在这项研究中，我们证明了朋友鼠逆转录病毒可以利用上述免疫逃避策略，正在进行的外周衰竭和病毒诱导的中枢耐受的组合。我们的数据表明，沿着外周衰竭T细胞的复苏，在考虑对嗜胸腺病原体慢性感染的免疫控制时，保留胸腺功能以提供病原体特异性幼稚T细胞可能是重要的。
In chronic viral infections, persistent antigen presentation causes progressive exhaustion of virus-specific CD8+ T cells. It has become clear, however, that virus-specific naïve CD8+ T cells newly generated from the thymus can be primed with persisting antigens. In the setting of low antigen density and resolved inflammation, newly primed CD8+ T cells are preferentially recruited into the functional memory pool. Thus, continual recruitment of naïve CD8+ T cells from the thymus is important for preserving the population of functional memory CD8+ T cells in chronically infected animals. Friend virus (FV) is the pathogenic murine retrovirus that establishes chronic infection in adult mice, which is bolstered by the profound exhaustion of virus-specific CD8+ T cells induced during the early phase of infection. Here we show an additional evasion strategy in which FV disseminates efficiently into the thymus, ultimately leading to clonal deletion of thymocytes that are reactive to FV antigens. Owing to the resultant lack of virus-specific recent thymic emigrants, along with the above exhaustion of antigen-experienced peripheral CD8+ T cells, mice chronically infected with FV fail to establish a functional virus-specific CD8+ T cell pool, and are highly susceptible to challenge with tumor cells expressing FV-encoded antigen. However, FV-specific naïve CD8+ T cells generated in uninfected mice can be primed and differentiate into functional memory CD8+ T cells upon their transfer into chronically infected animals. These findings indicate that virus-induced central tolerance that develops during the chronic phase of infection accelerates the accumulation of dysfunctional memory CD8+ T cells. During thymocyte development, cells that recognize self-antigens are specifically deleted by the process known as negative selection. However, some pathogens disseminate to the thymus, and can induce foreign antigen presentation within this organ, resulting in potentially harmful clonal deletion of pathogen-specific T-lymphocyte precursors. In chronic infections, pathogen-specific T cells in the periphery progressively lose their functionality due to continual stimulation with the persisting antigen, a phenomenon known as T cell exhaustion. However, pathogen-reactive naïve T cells freshly primed during the chronic phase of infection can nevertheless replenish the functional pool of memory T cells. Therefore, a lack of their generation in the face of peripheral exhaustion may ultimately cause the loss of functional memory T cells and the resultant lack of pathogen control. In this study, we demonstrate that Friend murine retrovirus can utilize the above immune evasion strategy, a combination of ongoing peripheral exhaustion and virus-induced central tolerance. Our data suggest that, along with the reinvigoration of exhausted T cells in the periphery, preservation of the thymic function in supplying pathogen-specific naïve T cells may be important when considering immunological control of chronic infection with thymotropic pathogens.
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DOI：
10.1073/pnas.1015148108
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