Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis
Circulating Senescent T Cells Are Linked to Systemic Inflammation and Lesion Size During Human Cutaneous Leishmaniasis
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DOI：
10.3389/fimmu.2018.03001
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发表时间：
2019-01-04
影响因子：
7.3
通讯作者：
Gomes, Daniel C. O.
中科院分区：
文献类型：
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作者：
Covre, Luciana P.;Martins, Regia F.;Gomes, Daniel C. O.
巴西利什曼原虫（Viannia）可诱发美洲外皮利什曼病，其严重程度从较轻的皮肤利什曼病（CL）到严重的播散性皮肤利什曼病不等。 CL 患者会产生细胞介导的 Th1 免疫反应，并伴有炎症细胞因子的产生，这有助于寄生虫控制和疾病发病机制。在这里，我们描述了具有端粒依赖性衰老多种特征的循环 T 细胞的积累，包括 CD57、KLRG-1 和 γ H2AX 表达升高，这些细胞在巴西乳杆菌皮肤感染期间具有短端粒和低 hTERT 表达。这种扩大的 T 细胞群存在于 CD45RA(+)CD27(-) (EMRA) 亚群中，并产生高水平的炎症细胞因子，类似于在衰老非淋巴细胞中描述的衰老相关分泌谱 (SASP)。这些细胞的积累与全身炎症的程度之间存在显着相关性，表明它们参与了这种疾病的炎症反应。此外，这些细胞表达高水平的皮肤归巢受体 CLA，并且循环中这些细胞的数量与利什曼原虫引起的皮肤损伤的大小之间存在高度显着的相关性。总的来说，我们的结果表明，利什曼病早期阶段的广泛激活会导致 T 细胞衰老，并倾向于回归皮肤。这些细胞分泌的衰老相关炎症细胞因子可能控制感染，但也有助于疾病的免疫病理学。
Leishmania (Viannia) braziliensis induces American tegumentary leishmaniasis that ranges in severity from the milder form, cutaneous (CL) to severe disseminated cutaneous leishmaniasis. Patients with CL develop a cell-mediated Th1 immune response accompanied by production of inflammatory cytokines, which contribute to parasite control and pathogenesis of disease. Here, we describe the accumulation of circulating T cells with multiple features of telomere dependent-senescence including elevated expression of CD57, KLRG-1, and gamma H2AX that have short telomeres and low hTERT expression during cutaneous L. braziliensis infection. This expanded population of T cells was found within the CD45RA(+)CD27(-) (EMRA) subset and produced high levels of inflammatory cytokines, analogous to the senescence-associated secretory profile (SASP) that has been described in senescent non-lymphoid cells. There was a significant correlation between the accumulation of these cells and the extent of systemic inflammation, suggesting that they are involved in the inflammatory response in this disease. Furthermore, these cells expressed high level of the skin homing receptor CLA and there was a highly significant correlation between the number of these cells in the circulation and the size of the Leishmania-induced lesions in the skin. Collectively our results suggest that extensive activation during the early stages of leishmaniasis drives the senescence of T cells with the propensity to home to the skin. The senescence-related inflammatory cytokine secretion by these cells may control the infection but also contribute to the immunopathology in the disease.