An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis

Bertrand Boisson, Chenhui Wang, Vincent Pedergnana, Ling Wu, Sophie Cypowyj, Michel Rybojad, Aziz Belkadi, Capucine Picard, Laurent Abel, Claire Fieschi, Anne Puel, Xiaoxia Li, Jean Laurent Casanova

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Abstract

Patients with inborn errors of interleukin-17F (IL-17F) or IL-17RA display chronic mucocutaneous candidiasis (CMC). We report a biallelic missense mutation (T536I) in the adaptor molecule ACT1 in two siblings with CMC. The mutation, located in the SEFIR domain, abolished the homotypic interaction of ACT1 with IL-17 receptors, with no effect on homodimerization. The patients' fibroblasts failed to respond to IL-17A and IL-17F, and their Tcells to IL-17E. By contrast, healthy individuals homozygous for the common variant D10N, located in the ACT1 tumor necrosis factor receptor-associated factor-interacting domain and previously associated with psoriasis, had impaired, but not abolished, responses to IL-17 cytokines. SEFIR-independent interactions of ACT1 with other proteins, such as CD40, heat shock protein 70 (HSP70) and HSP90, were not affected by the T536I mutation. Overall, human IL-17A and IL-17F depend on ACT1 to mediate protective mucocutaneous immunity. Moreover, other ACT1-dependent IL-17 cytokines seem to be largely redundant in host defense.

Original languageEnglish
Pages (from-to)676-686
Number of pages11
JournalImmunity
Volume39
Issue number4
DOIs
Publication statusPublished - 17 Oct 2013

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Boisson, B., Wang, C., Pedergnana, V., Wu, L., Cypowyj, S., Rybojad, M., Belkadi, A., Picard, C., Abel, L., Fieschi, C., Puel, A., Li, X., & Casanova, J. L. (2013). An ACT1 mutation selectively abolishes interleukin-17 responses in humans with chronic mucocutaneous candidiasis. Immunity, 39(4), 676-686. https://doi.org/10.1016/j.immuni.2013.09.002