DISCUSSION
The molecular and cellular basis of human CMC, which is common in patients with various conditions, was eventually deciphered thanks to the study of rare patients with CMCD, in whom CMC appears as the main clinical manifestation, without other severe infectious or autoimmune clinical signs (Puel et al., 2010b, 2012). Four genetic etiologies of CMCD have been described. AR IL-17RA and AD IL-17F deficiencies were the first two genetic etiologies to be discovered, through a candidate gene approach (Puel et al., 2011). IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers and to IL-17E/IL-25 (Puel et al., 2011; Boisson et al., 2013). In contrast, IL-17F deficiency is partial, with impairment but not total abolition of the activity of homo- and heterodimers containing the mutant IL-17F (Puel et al., 2011). Genome-wide approaches subsequently led to the discovery of heterozygous GOF mutations of STAT1 as the third and, to date, by far the most frequent genetic etiology of CMCD (Boisson-Dupuis et al., 2012). Stronger STAT1-dependent cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27 and to the STAT3-dependent IL-17 inducers IL-6, IL-21, and IL-23 may account for the poor development of IL-17–producing T cells observed in patients bearing such mutations (Liu et al., 2011). An AR deficiency of the adaptor molecule ACT1 was recently found in two siblings and identified as the fourth genetic etiology of CMCD (Boisson et al., 2013). The patients’ fibroblasts failed to respond to IL-17A and IL-17F, and their T cells did not respond to IL-17E/IL-25 (Boisson et al., 2013). We describe here AR complete IL-17RC deficiency, a new genetic etiology of CMCD, in three unrelated sporadic cases, further documenting the crucial role of human IL-17 immunity in mucocutaneous protection against C. albicans.
IL-17RC, one of the five members of the IL-17 receptor family, is a key component of the IL-17A and IL-17F receptor, as it forms a heterotrimeric receptor complex together with IL-17RA (Moseley et al., 2003; Toy et al., 2006; Weaver et al., 2007; Ely et al., 2009; Gaffen, 2009; Ho and Gaffen, 2010; Ho et al., 2010). Mouse IL-17RC (mIL-17RC), like mIL-17RA (McAllister et al., 2005), is essential for signaling downstream from mIL-17A, mIL-17F, and mIL-17A/F, both in vitro and in vivo (Ho and Gaffen, 2010; Hu et al., 2010), as in humans (Puel et al., 2011). However, mouse and human IL-17RC and IL-17RA have different binding affinities for IL-17A and IL-17F (Kuestner et al., 2007). In humans, IL-17RA binds preferentially to IL-17A and has a lower affinity for IL-17F (Wright et al., 2008). In contrast, IL-17RC binds IL-17A and IL-17F with a similar affinity (Kuestner et al., 2007; Ho and Gaffen, 2010). The opposite situation occurs in mice: mIL-17RA binds mIL-17A and mIL-17F with equal affinities, but mIL-17RC binds preferentially to mIL-17F (Kuestner et al., 2007; Ho and Gaffen, 2010). Moreover, after its heterodimerization with mIL-17RB, mIL-17RA has been shown to be involved in the IL-17E/IL-25 signaling pathway in mice (Rickel et al., 2008; Hu et al., 2010). Consistently, IL-17RA–deficient patients do not respond to IL-17E/IL-25 (Boisson et al., 2013). In contrast, mIL-17RC has not been shown to be part of another receptor (Ho and Gaffen, 2010), at least for mIL-17E/IL-25 signaling (Hu et al., 2011). We show here that IL-17E/IL-25 signaling is normal in humans with IL-17RC deficiency. Our findings demonstrate that human IL-17RC deficiency prevents cellular responses to IL-17A and IL-17F dimers but not to IL-17E/IL-25.
The infectious phenotype of the IL-17RC–deficient patients is consistent with that of mIL-17RC–deficient mice (Ho and Gaffen, 2010; Hu et al., 2010). IL-17RC–deficient mice displayed a large fungal burden in the oral cavity in a model of oropharyngeal candidiasis (OPC; Ho and Gaffen, 2010; Trautwein-Weidner et al., 2015). Likewise, the IL-17RC–deficient patients displayed recurrent or persistent oral candidiasis with or without skin and/or nail involvement from early infancy onward. This phenotype, restricted to isolated CMC, is similar to that of patients with AD IL-17F, AR IL-17RA, and AR ACT1 deficiencies (Puel et al., 2011; Boisson et al., 2013). However, patients with AR IL-17RA and AR ACT1 deficiencies also display peripheral staphylococcal infections, such as dermatitis (Puel et al., 2011) and blepharitis (Boisson et al., 2013). It is tempting to speculate that these infections might result, at least in part, from impaired IL-17E/IL-25 responses, which are normal in IL-17F– and IL-17RC–deficient patients. Susceptibility to cutaneous staphylococcal disease has been observed in mIL-17RA–deficient mice (Aujla et al., 2007; Curtis and Way, 2009; Vidlak and Kielian, 2012; Aldave et al., 2013). Spontaneous occurrence of peripheral S. aureus infection was also observed in double mIL-17A/mIL-17F but not in single mIL-17A or mIL-17F knockout mice (Ishigame et al., 2009). mIL-17RC– and mACT1-deficient mice have yet to be tested. Finally, patients with AD STAT1 GOF have a broader infectious phenotype, which is probably the result of the broader cellular impact of the mutations (unpublished data). Overall, our data demonstrate that human IL-17 signaling via IL-17RC is essential for mucocutaneous immunity to C. albicans, but suggest that this signaling is redundant for immunity to most other common pathogens, even possibly including S. aureus. Moreover, human IL-17RC is not required for cellular responses to IL-17E/IL-25.