Department of Immunology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Department of Medical Microbiology and Infectious Diseases, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
Nat Commun. 2023 Dec 19;14(1):8449. doi: 10.1038/s41467-023-44297-6.
Cutaneous Leishmania major infection elicits a rapid T cell response that is insufficient to clear residually infected cells, possibly due to the accumulation of regulatory T cells in healed skin. Here, we used Leishmania-specific TCR transgenic mice as a sensitive tool to characterize parasite-specific effector and immunosuppressive responses in vivo using two-photon microscopy. We show that Leishmania-specific Tregs displayed higher suppressive activity compared to polyclonal Tregs, that was mediated through IL-10 and not through disrupting cell-cell contacts or antigen presentation. In vivo expansion of endogenous Leishmania-specific Tregs resulted in disease reactivation that was also IL-10 dependent. Interestingly, lack of Treg expansion that recognized the immunodominant Leishmania peptide PEPCK was sufficient to restore robust effector Th1 responses and resulted in parasite control exclusively in male hosts. Our data suggest a stochastic model of Leishmania major persistence in skin, where cellular factors that control parasite numbers are counterbalanced by Leishmania-specific Tregs that facilitate parasite persistence.
皮肤利什曼原虫感染引发迅速的 T 细胞反应，但不足以清除残留感染的细胞，这可能是由于在愈合的皮肤中积累了调节性 T 细胞。在这里，我们使用利什曼原虫特异性 TCR 转基因小鼠作为一种敏感的工具，使用双光子显微镜在体内对寄生虫特异性效应器和免疫抑制反应进行了特征描述。我们表明，与多克隆 Treg 相比，利什曼原虫特异性 Treg 显示出更高的抑制活性，这种活性是通过 IL-10 介导的，而不是通过破坏细胞-细胞接触或抗原呈递来介导的。内源性利什曼原虫特异性 Treg 的体内扩增导致疾病复发，这也是 IL-10 依赖性的。有趣的是，缺乏识别免疫优势利什曼原虫肽 PEPCK 的 Treg 扩增足以恢复强大的效应 Th1 反应，并导致寄生虫在雄性宿主中得到有效控制。我们的数据提出了一种皮肤中利什曼原虫持续存在的随机模型，其中控制寄生虫数量的细胞因子与促进寄生虫持续存在的利什曼原虫特异性 Treg 相平衡。
