CD28 Costimulation Is Required for Development of Herpetic Stromal Keratitis but Does Not Prevent Establishment of Latency.
CD28 Costimulation Is Required for Development of Herpetic Stromal Keratitis but Does Not Prevent Establishment of Latency.
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CD28 共刺激对于疱疹性基质性角膜炎的发展是必需的，但不能阻止潜伏期的建立。
DOI：
10.1128/jvi.00659-19
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发表时间：
2019
影响因子：
5.4
通讯作者：
Stuart,PatrickM
中科院分区：
文献类型：
--
作者：
Yin,Xiao-Tang;Baugnon,NicholasK;Potter,ChloeA;Tai,Shannon;Keadle,TammieL;Stuart,PatrickM
单纯疱疹病毒 1 (HSV-1) 的角膜感染会导致三叉神经节 (TG) 感染，通常随后会在受感染的神经元中建立潜伏期。当潜伏期被破坏时，病毒会重新激活并迁移回角膜，在那里重新刺激免疫反应，导致疱疹性基质性角膜炎（HSK）疾病的病变。 HSK 需要 T 细胞激活，因为没有 T 细胞就没有疾病。我们决定确定 HSK 中是否需要 T 细胞的 CD28 共刺激。结果表明，C57BL/6 CD28−/− 和 BALB/c CD28−/− 小鼠未能出现复发性 HSK，而其野生型小鼠却出现了复发性 HSK。为了更好地了解这些小鼠中 TG 感染的动态，我们评估了受感染 TG 中的病毒量以及携带潜伏病毒的单个神经元的数量。结果表明，从第7天到第30天，CD28−/−小鼠的TG基因组水平显着增加，但LAT阳性细胞比野生型小鼠少得多，但在第30天后，这些差异变得不显着。接下来我们评估了 TG 中的总 CD8+T 细胞和抗原特异性 CD8+T 细胞。结果表明，从第10天到第25天，TG中的CD8 T细胞明显减少，但之后差异不显着。总而言之，这些数据表明 HSK 需要 CD28 共刺激，但虽然 CD28−/− 小鼠中 TG 的初始感染较多，但随着时间的推移，这种情况开始正常化，并且这种正常化与抗原特异性 CD8+T 细胞的延迟发育同时发生。 重要性我们研究单纯疱疹病毒介导的角膜疾病的发病机制。 T 细胞在疾病和神经元潜伏期的维持中都发挥着关键作用。因此，本研究的重点是评估 T 细胞共刺激在角膜疾病和控制病毒维持角膜神经节稳定感染的能力方面所发挥的作用。我们证明，在没有 CD28 共刺激的情况下，不会发生角膜疾病。然而，这种共刺激并不能阻止 CD8+T 细胞发育的能力，从而控制神经元的潜在感染。我们从这些研究中得出结论，CD28 共刺激是角膜破坏性免疫反应所必需的，但 CD8+T 细胞会随着时间的推移而发育，并有助于维持潜伏期。
Corneal infection with herpes simplex virus 1 (HSV-1) leads to infection of trigeminal ganglia (TG), typically followed by the establishment of latency in the infected neurons. When latency is disrupted, the virus reactivates and migrates back to the cornea, where it restimulates the immune response, leading to lesions in a disease called herpetic stromal keratitis (HSK). HSK requires T cell activation, as in the absence of T cells there is no disease. We decided to determine if CD28 costimulation of T cells was required in HSK. The results indicated that C57BL/6 CD28−/−and BALB/c CD28−/−mice failed to develop recurrent HSK, while their wild-type counterparts did. In order to better understand the dynamics of TG infection in these mice, we evaluated the amount of virus in infected TG and the number of individual neurons harboring latent virus. The results indicated that CD28−/−mice possessed significantly increased genome levels in their TG but many fewer LAT-positive cells than wild-type mice from day 7 to day 30 but that after day 30 these differences became nonsignificant. We next evaluated total and antigen-specific CD8+T cells in TG. The results indicated that there were significantly fewer CD8 T cells in TG from day 10 to day 25 but that after that the differences were not significant. Taken together, these data suggest that CD28 costimulation is required for HSK but that while initial infection of TG is greater in CD28−/−mice, this begins to normalize with time and this normalization is concurrent with the delayed development of antigen-specific CD8+T cells.IMPORTANCEWe study the pathogenesis of herpes simplex virus-mediated corneal disease. T cells play a critical role both in disease and in the maintenance of latency in neurons. Consequently, the focus of this study was to evaluate the role that T cell costimulation plays both in corneal disease and in controlling the ability of the virus to maintain a stable infection of the ganglia that innervate the cornea. We demonstrate that in the absence of costimulation with CD28, corneal disease does not take place. However, this costimulation does not prevent the ability of CD8+T cells to develop and, thus, control latent infection of neurons. We conclude from these studies that CD28 costimulation is required for corneal destructive immune responses but that CD8+T cells develop over time and help to maintain latency.