An ACT1 Mutation Selectively Abolishes Interleukin-17 Responses in Humans with Chronic Mucocutaneous Candidiasis

作者:Boisson Bertrand*; Wang Chenhui; Pedergnana Vincent; Wu Ling; Cypowyj Sophie; Rybojad Michel; Belkadi Aziz; Picard Capucine; Abel Laurent; Fieschi Claire; Puel Anne; Li Xiaoxia; Casanova Jean Laurent
来源:Immunity, 2013, 39(4): 676-686.
DOI:10.1016/j.immuni.2013.09.002

摘要

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 homo-dimerization. The patients%26apos; fibroblasts failed to respond to IL-17A and IL-17F, and their T cells 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.

  • 出版日期2013-10-17