Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.
Aberrant type 1 immunity drives susceptibility to mucosal fungal infections.
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DOI：
10.1126/science.aay5731
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发表时间：
2021-01-15
期刊：
影响因子：
--
通讯作者：
Lionakis MS
中科院分区：
文献类型：
--
作者：
Break TJ;Oikonomou V;Dutzan N;Desai JV;Swidergall M;Freiwald T;Chauss D;Harrison OJ;Alejo J;Williams DW;Pittaluga S;Lee CR;Bouladoux N;Swamydas M;Hoffman KW;Greenwell-Wild T;Bruno VM;Rosen LB;Lwin W;Renteria A;Pontejo SM;Shannon JP;Myles IA;Olbrich P;Ferré EMN;Schmitt M;Martin D;Genomics and Computational Biology Core;Barber DL;Solis NV;Notarangelo LD;Serreze DV;Matsumoto M;Hickman HD;Murphy PM;Anderson MS;Lim JK;Holland SM;Filler SG;Afzali B;Belkaid Y;Moutsopoulos NM;Lionakis MS
单基因疾病的研究揭示了免疫途径在人类组织特异性免疫和抗菌防御中的重要性。特别是，人类先天性白细胞介素-17（IL-17）受体信号传导途径的缺陷和小鼠研究的证实已经确立了17型反应在粘膜特异性真菌监测中的关键作用。酵母菌白色念珠菌是自身免疫性多内分泌病-念珠菌病-外胚层营养不良（APECED）的标志性病原体，APECED是一种由自身免疫调节因子（AIRE）基因功能缺失突变引起的遗传性自身免疫性疾病。APECED中的真菌病仅限于慢性粘膜皮肤念珠菌病（CMC），无播散，提示屏障免疫的中枢缺陷。AIRE缺陷损害中枢免疫耐受，导致产生针对许多组织特异性抗原和某些细胞因子（包括“17型”细胞因子）的致病性自身反应性T细胞和自身抗体。然而，尽管大多数患有CMC的APECED患者具有17型精氨酸靶向自身抗体，但AIRE缺乏症是否影响17型或其他局部粘膜免疫应答尚未确定。在这里，我们广泛研究了在Aire−/−小鼠口咽念珠菌病模型和APECED患者的大队列中的口腔粘膜免疫反应。在AIRE缺乏的小鼠和人类中，口腔粘膜的17型免疫应答出乎意料地完整。为了确定真菌易感性的替代机制，我们研究了Aire−/−小鼠，其表现出口腔粘膜特异性对念珠菌病的易感性，而没有传播，并正常控制病毒和细菌的实验挑战，从而模拟了在APECED患者中观察到的感染倾向。值得注意的是，Aire−/− CD 4+和CD 8 + T细胞数量增加，并在口腔粘膜内显示出活化和增殖表型，这是Aire缺乏症中驱动粘膜真菌感染的必要和充分条件。Aire−/−粘膜CD 4+和CD 8 + T细胞产生干扰素-γ（IFN-γ）的增强导致口腔粘膜中IFN-γ/STAT 1介导的反应加剧，从而促进IFN-γ依赖性上皮屏障破坏和粘膜真菌易感性。IFN-γ或JAK-STAT信号传导的遗传和药理学抑制改善了Aire−/−小鼠的粘膜真菌病。在APECED患者的口腔粘膜中也观察到异常的1型反应。我们确定T细胞依赖性干扰素病是APECED中CMC的关键局部粘膜机制。虽然17型粘膜免疫对于宿主防御屏障感染至关重要，但在APECED患者和该疾病的小鼠模型中，17型粘膜反应是完整的。这些发现表明，与已知的T细胞在抗真菌宿主防御中的保护作用相反，异常的1型相关T细胞应答可能对抗真菌粘膜免疫有害。他们还支持一个范例，夸张的免疫病理学可能会促进粘膜真菌感染的易感性，损害上皮屏障的完整性。最后，他们为研究其他CMC表现疾病中的1型粘膜反应以及使用FDA批准的靶向IFN-γ或JAK-STAT信号传导的疗法预防和治疗APECED患者中的CMC铺平了道路。人类单基因疾病揭示了17型反应在粘膜真菌监测中的关键贡献。我们意外地发现，在某些情况下，增强的1型免疫而不是有缺陷的17型反应可以促进粘膜真菌感染的易感性。值得注意的是，在患有AIRE缺乏症的小鼠和人类中，一种自身免疫性疾病，其特征在于对粘膜而非全身性真菌感染的选择性易感性，粘膜17型反应是完整的，而1型反应是恶化的。这些反应促进异常干扰素-γ（IFN-γ）和信号转导和转录激活因子1（STAT 1）依赖性上皮屏障缺陷以及粘膜真菌感染易感性。一致地，IFN-γ或Janus激酶（JAK）-STAT信号传导的遗传和药理学抑制改善粘膜真菌疾病。因此，我们确定异常的T细胞依赖性，1型粘膜炎症作为一个关键的组织特异性致病机制，促进粘膜真菌感染的易感性，在小鼠和人类。异常的1型粘膜免疫是粘膜真菌易感性的基础。左图：17型粘膜反应促进粘膜真菌清除。右：在AIRE缺陷中，T细胞驱动增强的IFN-γ/STAT 1依赖性粘膜应答，其破坏上皮屏障并在完整的17型粘膜应答的情况下促进真菌易感性。AIRE，自身免疫调节因子; pSTAT 1，磷酸化信号转导和转录激活因子1; ILC，先天性淋巴样细胞。
Studies of monogenic diseases have uncovered the importance of immune pathways in human tissue-specific immunity and antimicrobial defense. In particular, human inborn errors of the interleukin-17 (IL-17) receptor signaling pathway and corroborating mouse studies have established the critical contribution of type 17 responses inmucosa-specific fungal surveillance. The yeast Candida albicans is the signature pathogen in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), an inherited autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. Fungal disease in APECED is limited to chronic mucocutaneous candidiasis (CMC) without dissemination, suggesting a central defect in barrier immunity. AIRE deficiency impairs central immune tolerance, resulting in the generation of pathogenic autoreactive T cells and autoantibodies directed against many tissue-specific antigens and certain cytokines, including “type 17” cytokines. However, although a majority of APECED patients with CMC have type 17 cytokine–targeted autoantibodies, whether type 17 or other localmucosal immune responses are affected in AIRE deficiency has not been determined. Here, we broadly investigated oral mucosal immune responses both in a model of oropharyngeal candidiasis in Aire−/− mice and in a large cohort of APECED patients. Type 17 immune responses at the oralmucosa were unexpectedly intact in mice and humans with AIRE deficiency. To define alternative mechanisms of fungal susceptibility, we investigated Aire−/− mice, which exhibited oralmucosa-specific susceptibility to candidiasis without dissemination and controlled experimental challenges with viruses and bacteria normally, thereby phenocopying the infection predisposition observed in APECED patients. Notably, Aire−/− CD4+ and CD8+ T cells accumulated in increased numbers and displayed an activated and proliferative phenotype within the oral mucosa and were both necessary and sufficient to drive mucosal fungal infection in Aire deficiency. Enhanced production of interferon-γ (IFN-γ) by Aire−/− mucosal CD4+ and CD8+ T cells resulted in exacerbated IFN-γ/STAT1-mediated responses in the oral mucosa, which promoted IFN-γ–dependent epithelial barrier disruption and mucosal fungal susceptibility. Genetic and pharmacologic inhibition of IFN-γ or JAK-STAT signaling ameliorated mucosal fungal disease in Aire−/− mice. Aberrant type 1 responseswere also observed in the oral mucosa of APECED patients. We identify a T cell–dependent interferonopathy as a critical local mucosal mechanism underlying CMC in APECED. Although type 17 mucosal immunity is critical for host defense against barrier infection, mucosal type 17 responses were intact in patients with APECED and in a mouse model of the disease. These findings show that, in contrast to the known protective roles of T cells in antifungal host defense, aberrant type 1–associated T cell responses can be detrimental to antifungal mucosal immunity. They also support a paradigm by which exaggerated immunopathology may facilitate susceptibility to mucosal fungal infection by impairing the integrity of the epithelial barrier. Finally, they pave the way for investigating type 1 mucosal responses in other CMC-manifesting diseases and for the prevention and treatment of CMC in APECED patients using FDA-approved therapies that target IFN-γ or JAK-STAT signaling. Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)– and signal transducer and activator of transcription 1 (STAT1)–dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)–STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell–dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans. Aberrant type 1 mucosal immunity underlies mucosal fungal susceptibility. Left: Type 17 mucosal responses promote mucosal fungal clearance. Right: In AIRE deficiency, T cells drive enhanced IFN-γ/STAT1-dependent mucosal responses that disrupt the epithelial barrier and promote fungal susceptibility in the setting of intact type 17 mucosal responses. AIRE, autoimmune regulator; pSTAT1, phosphorylated signal transducer and activator of transcription 1; ILCs, innate lymphoid cells.
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影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP
影响因子：
12.8
作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
8
作者：
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通讯作者：
Lionakis, Michail S.