Type 1 immunity gives fungi a foothold Type 17 immune responses play a vital role against fungal infections of the mucosa. It remains unclear whether other types of immune responses can also contribute to host defense against these pathogens. The yeast Candida albicans prominently infects patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), an inherited disease caused by loss-of-function mutations in the AIRE gene. Break et al. report that the oral susceptibility of Aire-deficient mice to C. albicans is not due not to aberrant type 17 responses. Rather, the overproduction of interferon-γ by local CD4+ and CD8+ T cells in these mice disrupts the epithelial barrier, which increases susceptibility to C. albicans invasion. Similar type 1 immune pathways are operational in APECED patients. Inhibition of interferon-γ or the JAK-STAT signaling pathway in mice ameliorates disease symptoms, suggesting potential future therapeutic interventions for certain classes of fungal disease. Science, this issue p. eaay5731 T cell–dependent, type 1–mediated mucosal inflammation promotes mucosal fungal susceptibility in mice and humans. INTRODUCTION 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 in mucosa-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. RATIONALE 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 local mucosal 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. RESULTS Type 17 immune responses at the oral mucosa were unexpectedly intact in mice and humans with AIRE deficiency. To define alternative mechanisms of fungal susceptibility, we investigated Aire–/– mice, which exhibited oral mucosa-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 responses were also observed in the oral mucosa of APECED patients. CONCLUSION 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. 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. 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.

中文翻译：

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异常的 1 型免疫导致对粘膜真菌感染的易感性


1 型免疫为真菌提供了立足点。17 型免疫反应在对抗粘膜真菌感染方面发挥着至关重要的作用。目前尚不清楚其他类型的免疫反应是否也有助于宿主防御这些病原体。白色念珠菌主要感染患有自身免疫性多内分泌病-念珠菌病-外胚层营养不良症 (APECED) 的患者，这是一种由 AIRE 基因功能丧失突变引起的遗传性疾病。布雷克等人。报道称，Aire 缺陷小鼠对白色念珠菌的口腔易感性并非由于异常的 17 型反应所致。相反，这些小鼠中局部 CD4+ 和 CD8+ T 细胞过量产生干扰素-γ，破坏了上皮屏障，从而增加了白色念珠菌入侵的易感性。类似的 1 型免疫途径在 APECED 患者中发挥作用。抑制小鼠体内的干扰素-γ 或 JAK-STAT 信号通路可改善疾病症状，这表明未来可能对某些类型的真菌疾病进行治疗干预。科学，本期第 14 页。 eaay5731 T 细胞依赖性、1 型介导的粘膜炎症可促进小鼠和人类的粘膜真菌敏感性。引言 单基因疾病的研究揭示了免疫途径在人体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) 受体信号通路缺陷和小鼠研究证实了 17 型反应在粘膜特异性真菌监测中的关键作用。酵母白色念珠菌是自身免疫性多内分泌病-念珠菌病-外胚层营养不良症 (APECED) 的标志性病原体，这是一种由自身免疫调节器 (AIRE) 基因功能丧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皮肤粘膜念珠菌病 (CMC)，没有播散，表明屏障免疫存在中心缺陷。基本原理 AIRE 缺陷会损害中枢免疫耐受，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 型细胞因子靶向自身抗体，但 AIRE 缺陷是否影响 17 型或其他局部粘膜免疫反应尚未确定。在这里，我们广泛研究了 Aire-/- 小鼠口咽念珠菌病模型和一大群 APECED 患者的口腔粘膜免疫反应。结果 在患有 AIRE 缺陷的小鼠和人类中，口腔粘膜的 17 型免疫反应出乎意料地完好无损。为了确定真菌易感性的替代机制，我们研究了 Aire–/– 小鼠，该小鼠表现出口腔粘膜对念珠菌病的特异性易感性，但没有传播，并控制了正常病毒和细菌的实验挑战，从而对 APECED 患者中观察到的感染倾向进行表型复制。值得注意的是，Aire–/– CD4+ 和 CD8+ T 细胞的数量增加，并在口腔粘膜内表现出激活和增殖的表型，并且对于驱动 Aire 缺陷的粘膜真菌感染是必要且充分的。 Aire–/– 粘膜 CD4+ 和 CD8+ T 细胞产生的干扰素-γ (IFN-γ) 增强，导致口腔粘膜中 IFN-γ/STAT1 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损伤。真菌敏感性。 IFN-γ 或 JAK-STAT 信号传导的遗传和药理学抑制可改善 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。结论 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。尽管 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 细胞反应可能不利于抗真菌粘膜免疫。他们还支持一种范式，即夸大的免疫病理学可能通过损害上皮屏障的完整性而促进对粘膜真菌感染的易感性。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 批准的针对 IFN-γ 或 JAK-STAT 信号传导的疗法预防和治疗 APECED 患者的 CMC 铺平了道路。异常的 1 型粘膜免疫是粘膜真菌易感性的基础。左：17 型粘膜反应促进粘膜真菌清除。右图：在 AIRE 缺陷中，T 细胞驱动增强的 IFN-γ/STAT1 依赖性粘膜反应，破坏上皮屏障并在完整的 17 型粘膜反应环境中促进真菌敏感性。 AIRE，自身免疫调节器； pSTAT1，磷酸化信号转导子和转录激活子 1； ILC，先天淋巴细胞。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 缺陷（一种以选择性易感粘膜而非全身真菌感染为特征的自身免疫性疾病）的小鼠和人类中，粘膜 17 型反应完整，而 1 型反应加剧。这些反应促进异常干扰素-γ (IFN-γ) 和信号转导子和转录激活子 1 (STAT1) 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可改善粘膜真菌病。因此，我们将异常 T 细胞依赖性 1 型粘膜炎症确定为一种关键的组织特异性致病机制，可促进小鼠和人类粘膜真菌感染的易感性。