Mucosal Immunology | VOLUME 3 NUMBER 4 | JULY 2010 361 nature publishing group ARTICLES INTRODUCTION Candida albicans is a human commensal of mucosal and skin surfaces. A number of dysregulated immune reactivities has been associated with the fungus and/or certain fungal compo- nents. 1 We have shown that the activation of Th17 cells at sites of infection may contribute to inflammatory pathology and worsens fungal diseases. 2 However, the role of IL-17 and Th17 cells in immunity vs. pathology in candidiasis remains contro- versial. 3 Although Th17 are present in the human T cell memory repertoire to the fungus 4 and defective Th17 cell differentia- tion has been linked to mucocutaneous candidiasis in patients with primary immunodeficiencies, 5–7 the role of IL-17/Th17 in human candidiasis is not so unambiguously defined. Similarly, both positive and negative effects on immune resistance have been attributed to Th17 and IL-17 receptor (IL-17R) signaling in experimental candidiasis. 2,8–10 Given the importance of IL-17 in recruiting myeloid cells to sites of infection and because defective neutrophil recruitment underlined the susceptibility of IL-17R-deficient mice to dissem- inated 9 or oral 8 candidiasis, it is assumed that the very absence of Th17 cells is directly responsible for the increased susceptibility to candidiasis. Somehow paradoxical, however, administration of exogenous IL-17 not only did not rescue the Th17 deficiency in oral candidiasis but induced systemic inflammatory effects. 8 We have found that neutralization of IL-17A greatly reduced fungal burden, and corrected inflammation while concomitantly reducing neutrophil recruitment and Th17 cell activation. 2,11 The mechanisms that linked innate immunity and inflamma- tion to chronic infection have been credited to the offending potential of IL-17A that, although promoting neutrophil recruit- ment, impeded the timely restriction of neutrophil inflamma- tory potential, thus preventing optimal protection to occur. 12 Th17 cells also produce IL-22, a member of the IL-10 family of cytokines, which has been shown to have a more important role than IL-17 in host defense in the lung and gut. 13–15 However, the role of IL-22 in inflammatory responses has been confounded by data suggesting both pro- and anti-inflammatory functions. The finding that IL-23 was protective in condition of IFN-  deficiency 2 suggest that IL-23 may regulate the production of cytokines other than IL-17A/IL-17F. Herein, we provide evi- dence that IL-22 has a first-line defense in candidiasis by criti- cally controlling initial fungal growth and epithelial homeostasis in the relative absence of Th1 immunity. The two pathways are reciprocally regulated, being the IL-23/IL-22 pathway upregu- lated in Th1-deficiency and the Th1 pathway in IL-22 deficiency, and compensate each other in the relative absence of either one. IL-22 defines a novel immune pathway of antifungal resistance A De Luca 1,3 , T Zelante 1,3 , C D’Angelo 1 , S Zagarella 1 , F Fallarino 1 , A Spreca 1 , RG Iannitti 1 , P Bonifazi 1 , J-C Renauld 2 , F Bistoni 1 , P Puccetti 1 and L Romani 1 The role of IL-17 and Th17 cells in immunity vs. pathology associated with the human commensal Candida albicans remains controversial. Both positive and negative effects on immune resistance have been attributed to IL-17/Th17 in experimental candidiasis. In this study, we provide evidence that IL-22, which is also produced by Th17 cells, has a critical, first-line defense in candidiasis by controlling the growth of infecting yeasts as well as by contributing to the host’ s epithelial integrity in the absence of acquired Th1-type immunity. The two pathways are reciprocally regulated, and IL-22 is upregulated under Th1 deficiency conditions and vice versa. Whereas both IL-17A and F are dispensable for antifungal resistance, IL-22 mediates protection in IL-17RA-deficient mice, in which IL-17A contributes to disease susceptibility. Thus, our findings suggest that protective immunity to candidiasis is made up of a staged response involving an early, IL-22-dominated response followed by Th1/Treg reactivity that will prevent fungal dissemination and supply memory. 1 Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy . 2 Ludwig Institute for Cancer Research Ltd Experimental Medicine Unit, Universite Catholique de Louvain, Brussels, Belgium. 3 These authors contributed equally to this work. Correspondence: L Romani (lromani@unipg.it) Received 10 February 2010; accepted 5 April 2010; published online 5 May 2010. doi:10.1038/mi.2010.22