Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. We found here that the IL‐23/IL‐17 developmental pathway acted as a negative regulator of the Th1‐mediated immune resistance to fungi and played an inflammatory role previously attributed to uncontrolled Th1 cell responses. Both inflammation and infection were exacerbated by a heightened Th17 response against Candida albicans and Aspergillus fumigatus, two major human fungal pathogens. IL‐23 acted as a molecular connection between uncontrolled fungal growth and inflammation, being produced by dendritic cells in response to a high fungal burden and counter‐regulating IL‐12p70 production. Both IL‐23 and IL‐17 subverted the inflammatory program of neutrophils, which resulted in severe tissue inflammatory pathology associated with infection. Our data are the first demonstrating that the IL‐23/IL‐17 pathway promotes inflammation and susceptibility in an infectious disease model. As IL‐23‐driven inflammation promotes infection and impairs antifungal resistance, modulation of the inflammatory response represents a potential strategy to stimulate protective immune responses to fungi.See accompanying commentary: http://dx.doi.org/10.1002/eji.200737804

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.

The ability of the fungus Aspergillus fumigatus to activate, suppress, or subvert host immune response during life cycle in vivo through dynamic changing of cell wall structure and secretion implicates discriminative immune sensing of distinct fungal components. In this study, we have comparatively assessed secreted- and membrane-anchored proteins, glycolipids, and polysaccharides for the ability to induce vaccine-dependent protection in transplanted mice and Th cytokine production by human-specific CD4+ T cell clones. The results show that the different fungal components are endowed with the distinct capacity to activate Th cell responses in mice and humans, with secreted proteins inducing Th2 cell activation, membrane proteins Th1/Treg, glycolipids Th17, and polysaccharides mostly IL-10 production. Of interest, the side-by-side comparison revealed that at least three fungal components (a protease and two glycosylphosphatidylinositol-anchored proteins) retained their immunodominant Th1/Treg activating potential from mice to humans. This suggests that the broadness and specificity of human T cell repertoire against the fungus could be selectively exploited with defined immunoactive Aspergillus Ags.

The ability of regulatory T (Treg) cells to inhibit aspects of innate and adaptive immunity is central to their protective function in fungal infections. In murine candidiasis, CD4+CD25+ Treg cells prevent excessive inflammation but enable fungal persistence in the gastrointestinal tract, which underlies the onset of durable antifungal protection. In this study, we show that fungal growth, inflammatory immunity, and tolerance to the fungus were all controlled by the coordinate activation of naturally occurring Treg cells, which limited early inflammation at the sites of infection, and pathogen-induced Treg cells (that regulated the expression of adaptive Th immunity in secondary lymphoid organs). Naturally occurring Treg cells required the TRIF pathway for migration to inflamed sites, where the MyD88 pathway would then restrain their suppressive function. Subsequent inflammatory Th1-type immunity was modulated by induced Treg cells, which required the TRIF pathway as well, and acted through activation of IDO in dendritic cells and Th17 cell antagonism. In vitro, using naive CD4+ cells from TRIF-deficient mice, tryptophan metabolites were capable of inducing the Foxp3-encoding gene transcriptionally and suppressing the gene encoding RORγt, Th17 lineage specification factor. This is the first study to show that the same tryptophan catabolites can foster dendritic cell-supported generation of Foxp3+ cells and mediate, at the same time, inhibition of RORγt-expressing T cells.

IntroductionThe induction of tolerance is central to the maintenance of immune homeostasis. Not only are dendritic cells (DCs) key elements in the development of immunity, but they also participate in the generation and maintenance of immune tolerance. Many studies have demonstrated a pivotal role for the enzyme indoleamine 2,3-dioxygenase (IDO) in immune regulation during infection, pregnancy, autoimmunity, transplantation, and neoplasia. 1,2 IDO is widely expressed in a variety of human tissues as well as in macrophages and DCs and is induced in inflammatory states via type I or type II IFN signaling. Through localized tryptophan deficiency combined with the release of proapoptotic kynurenines, DCs exert an IDO-dependent homeostatic control over the proliferation and survival of peripheral T cells and promote antigen-specific tolerance. 3,4 Murine plasmacytoid DCs (pDCs), which produce and respond to type I IFNs, have been credited with a unique ability to express functional IDO, implying an important role for these cells in the maintenance of peripheral tolerance. 5 DCs are now being exploited to improve vaccine efficacy. 6 Pathogen-pulsed DCs act, indeed, as a potent fungal vaccine in experimental hematopoietic stem cell transplantation (HSCT). 7 Protection is associated with myeloid and T-cell recovery, the activation of CD4 ϩ T-helper type 1 (Th1) lymphocytes, and the concomitant production of IL-10. This cytokine is required for the induction of regulatory T (Treg) cells, which have important functions in immune homeostasis including the onset of transplantation tolerance, inhibition of inflammation, and prevention of graft-versus-host disease (GVHD) lethality and leukemia relapse. [8][9][10] As tolerance is also one major requirement of a successful immune response to fungi, 11-13 tolerogenic DCs, including pDCs, may be pivotal in the generation of some form of dominant regulation that ultimately controls inflammation, pathogen immunity, and tolerance in transplant recipients. 14 Thymosin ␣1 (T␣1) is a naturally occurring thymic peptide 15 that promotes activation and cytokine production in human and murine mature DCs by signaling through Toll-like receptors (TLRs), including TLR9. 16 By influencing the balance of IL-12-and IL-10-producing DCs, T␣1 acts as an immune regulator capable of inducing protective immunity to Aspergillus fumigatus. 16 TLR9 stimulation can also lead to IDO activation via mechanisms including autocrine type I IFN signaling 17,18 and can promote pDC-mediated generation of CD4 ϩ CD25 ϩ cells, 19 which are an essential component of the IDO-dependent protective immunity to fungi. [11][12][13] We hypothesized that T␣1 could affect the balance of immunity and tolerance by DCs and the generation of Treg cells. We assessed here the effects of T␣1 on deriving DCs from bone marrow (murine) or peripheral blood (human) L.R. and P.P. devised the study, critically evaluated the data at regular intervals, and drafted the paper. L.R. takes responsibility for integrity of the work as a whole. K.P....