CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production
CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production
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DOI：
10.1371/journal.ppat.1006196
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发表时间：
2017-02-01
期刊：
影响因子：
6.7
通讯作者：
Scott, Phillip
中科院分区：
文献类型：
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作者：
Novais, Fernanda O.;Carvalho, Augusto M.;Scott, Phillip
失调的CD 8 + T细胞的细胞毒性在几种情况下在提高疾病严重程度中起着核心作用。然而，我们对细胞毒性导致免疫病理学发展的机制知之甚少。使用原生动物寄生虫利什曼原虫诱导的小鼠炎症模型和从皮肤利什曼病患者获得的数据，我们发现了NLRP 3炎性小体激活和IL-1 β释放作为CD 8 + T细胞介导的细胞毒性的有害后果的先前未被认识的作用，最终导致慢性炎症。重要的是，NLRP 3或IL-1 β的药理学阻断显著改善了利什曼病感染小鼠中CD 8 + T细胞驱动的免疫病理学。证实了这些发现与人类利什曼病的相关性，阻断来自利什曼病感染患者的皮肤活检组织中的NLRP 3炎性体阻止了IL-1 β的释放。因此，这些研究将CD 8 + T细胞的细胞毒性与炎性小体活化联系起来，并揭示了治疗皮肤利什曼病以及其中CD 8 + T细胞介导的细胞毒性诱导病理的其他疾病的新途径。
Deregulated CD8+ T cell cytotoxicity plays a central role in enhancing disease severity in several conditions. However, we have little understanding of the mechanisms by which immunopathology develops as a consequence of cytotoxicity. Using murine models of inflammation induced by the protozoan parasite leishmania, and data obtained from patients with cutaneous leishmaniasis, we uncovered a previously unrecognized role for NLRP3 inflammasome activation and IL-1 beta release as a detrimental consequence of CD8+ T cell-mediated cytotoxicity, ultimately resulting in chronic inflammation. Critically, pharmacological blockade of NLRP3 or IL-1 beta significantly ameliorated the CD8+ T cell-driven immunopathology in leishmania-infected mice. Confirming the relevance of these findings to human leishmaniasis, blockade of the NLRP3 inflammasome in skin biopsies from leishmania-infected patients prevented IL-1 beta release. Thus, these studies link CD8+ T cell cytotoxicity with inflammasome activation and reveal novel avenues of treatment for cutaneous leishmaniasis, as well as other of diseases where CD8+ T cell-mediated cytotoxicity induces pathology.