Research Article

Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

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Science  15 Jan 2021:
Vol. 371, Issue 6526, eaay5731
DOI: 10.1126/science.aay5731

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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 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.

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Structured Abstract

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.

Abstract

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.

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