Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection
Clonally expanded γδ T cells protect against Staphylococcus aureus skin reinfection
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DOI：
10.1172/jci96481
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发表时间：
2018-03-01
影响因子：
15.9
通讯作者：
Miller, Lloyd S.
中科院分区：
文献类型：
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作者：
Dillen, Carly A.;Pinsker, Bret L.;Miller, Lloyd S.
介导针对金黄色葡萄球菌皮肤再感染的持久保护的机制尚不清楚，因为尽管抗体滴度和记忆 T 细胞很高，但复发很常见。在这里，我们开发了金黄色葡萄球菌皮肤再感染的小鼠模型来研究保护性记忆反应。与WT小鼠相比，IL-1β缺陷小鼠在初次感染期间表现出较差的中性粒细胞募集和细菌清除能力，但在继发性金黄色葡萄球菌攻击期间得到了挽救。来自皮肤引流淋巴结的 γ δ T 细胞利用补偿性 T 细胞固有的 TLR2/MyD88 信号传导，通过运输和产生 TNF 和 IFN-γ 来介导救援，从而恢复中性粒细胞募集并促进细菌清除。 LN 的 RNA 测序 (RNA-seq) 显示克隆型金黄色葡萄球菌诱导的 yo T 细胞扩增，其互补决定区 3 (CDR3) aa 序列与不变的 V gamma 5* 树突状表皮 T 细胞相同。然而，显性 CDR3 序列的 T 细胞受体 γ (TRG) a 序列是由 TRGVS 和 TRGV6 的多个基因重排产生的，表明克隆型扩展。产生 TNF 和 IFN-γ 的 γ δ T 细胞也在缺乏 IRAK4 的人的外周血中扩增，这些人不再容易受到金黄色葡萄球菌皮肤感染。因此，克隆扩增的 γ δ T 细胞代表了针对复发性金黄色葡萄球菌皮肤感染的持久免疫机制。
The mechanisms that mediate durable protection against Staphylococcus aureus skin reinfections are unclear, as recurrences are common despite high antibody titers and memory T cells. Here, we developed a mouse model of S. aureus skin reinfection to investigate protective memory responses. In contrast with WT mice, IL-1 beta-deficient mice exhibited poor neutrophil recruitment and bacterial clearance during primary infection that was rescued during secondary S. aureus challenge. The gamma delta T cells from skin-draining LNs utilized compensatory T cell-intrinsic TLR2/MyD88 signaling to mediate rescue by trafficking and producing TNF and IFN-gamma, which restored neutrophil recruitment and promoted bacterial clearance. RNA-sequencing (RNA-seq) of the LNs revealed a clonotypic S. aureus-induced yo T cell expansion with a complementarity-determining region 3 (CDR3) aa sequence identical to that of invariant V gamma 5* dendritic epidermal T cells. However, this T cell receptor gamma (TRG) aa sequence of the dominant CDR3 sequence was generated from multiple gene rearrangements of TRGVS and TRGV6, indicating clonotypic expansion. TNF- and IFN-gamma-producing gamma delta T cells were also expanded in peripheral blood of IRAK4-deficient humans no longer predisposed to S. aureus skin infections. Thus, clonally expanded gamma delta T cells represent a mechanism for long-lasting immunity against recurrent S. aureus skin infections.