Immunity to infection in IL-17-deficient mice and humans

Abstract

Mice with defective IL-17 immunity display a broad vulnerability to various infectious agents at diverse mucocutaneous surfaces. In humans, the study of patients with various primary immunodeficiencies, including autosomal dominant hyper-IgE syndrome caused by dominant-negative STAT3 mutations and autosomal recessive autoimmune polyendocrinopathy syndrome type 1 caused by null mutations in AIRE, has suggested that IL-17A, IL-17F and/or IL-22 are essential for mucocutaneous immunity to Candida albicans. This hypothesis was confirmed by the identification of rare patients with chronic mucocutaneous candidiasis (CMC) due to autosomal recessive IL-17RA deficiency and autosomal dominant IL-17F deficiency. Heterozygosity for gain-of-function mutations in STAT1 in additional patients with CMC was recently shown to inhibit the development of IL-17 T cells. Although the infectious phenotype of patients with CMC and inborn errors of IL-17 immunity remains to be finely delineated, it appears that human IL-17A and IL-17F display redundancy for protective immunity in natural conditions that is not seen in their mouse orthologs in experimental conditions.

Schematic representation of IL-17 immunity, and cooperation between cells recognizing C. albicans (phagocytes and epithelial cells) and cells producing IL-17 cytokines (T and innate (NK) lymphocytes). Upon C. albicans recognition by PRRs (pathogen recognition receptors, including Dectin-1, Dectin-2, or the mannose receptor (MR)), adaptor molecules, such as CARD9, mediate via the NF-κB and AP-1 pathways the induction of pro-inflammatory cytokines by myeloid or epithelial cells. These pro-inflammatory cytokines, such as IL-6 or IL-23, activate T lymphocytes via STAT3 resulting in cell differentiation into IL-17-producing T cells. CMCD-causing mutations (in blue) in IL-17F and IL-17RA impair IL-17 function and response, respectively. CMCD-causing GOF mutations (also shown in blue) in STAT1 impair the development of IL-17 producing T cells.