The inflammatory response to fungi may serve to limit infection but may also contribute to pathogenicity, as documented by the occurrence of severe fungal infections in patients with immunoreconstitution disease (Cheng et al., 2000). These patients may experience intractable fungal infections despite recovery from neutropenia and the occurrence of adaptive immune responses. The above considerations imply that immunoregulation may be essential in fine-tuning inflammation and adaptive Th reactivity to fungi and fungal diseases. This imposes a new job upon the immune system. In addition to efficient control of pathogens, tight regulatory mechanisms are required in order to balance protective immunity and immunopathology. To limit the pathologic consequences of an excessive inflammatory cell-mediated reaction, the immune system resorts to a number of protective mechanisms. CD4+ T cells making immunoregulatory cytokines such as IL-10, transforming growth factor (TGF)-P and IL-4 have long been known and discussed in terms of immune deviation or class regulation. Recently, Treg cells, capable of fine-tuning protective antimicrobial immunity in order to minimize harmful immune pathology, have become an integral component of the immune response (Montagnoli et al., 2002; Montagnoli et al., 2006; Romani & Puccetti, 2006b; Hori et al., 2002; Cavassani et al., 2006; McKinley et al., 2006). The decision of how to respond will still be primarily determined by interactions between pathogens and cells of the innate immune system, but the actions of Treg cells will feed back into this dynamic equilibrium to regulate subsequent immune responses. Usually, Treg cells serve to restrain exuberant immune reactivity, which in many chronic infections benefits the host by limiting tissue damage. However, the natural Treg cell responses may handicap the efficacy of protective immunity. Conceptually, similar to their effect on immunity against pathogens, Treg cells can also impede effective immunosurveillance of tumors. Nowadays, aberrant numbers and/or functions of Treg cells are incorporated within the view of counter-regulatory elements affecting the self versus nonself discrimination and influencing the outcome of infection, autoimmunity, transplantation, cancer, and even allergy.
A number of clinical observations suggest an inverse relationship between IFN-y and IL-10 production in patients with fungal infections. High levels of IL-10, negatively affecting IFN-y production, are detected in chronic candidal diseases, in the severe form of endemic mycoses and in neutropenic patients with aspergillosis (Romani, 2004b). Fungal polysaccharides are known to negatively modulate CMI through the production of IL-10, a finding suggesting that IL-10 production may be a consequence of infection (Romani & Puccetti, 2006b). However, tolerance to fungi can also be achieved through the induction of Treg cells capable of finely tuning antifungal Th reactivity. Naturally occurring Treg cells operating in the respiratory or the gastrointestinal mucosa accounted for the lack of pathology associated with fungal clearance in mice with fungal pneumonia or mucosal candidiasis (Montagnoli et al., 2002, 2006). Distinct Treg populations capable of mediating anti-inflammatory or tolerogenic effects are coordi-nately induced after exposure to Aspergillus conidia. Ultimately, the inherent resistance to Aspergillus diseases suggests the existence of regulatory mechanisms that provide the host with protection from infection and tolerance to allergy. It has been demonstrated that a division of labor occurs between functionally distinct Treg cells that are coordinately activated after exposure of mice to Aspergillus resting conidia. Early in infection, inflammation is controlled by the expansion, activation, and local recruitment of Treg cells suppressing neutrophils through the combined actions of IL-10 and cytotoxic T lymphocyte antigen-4 on the enzyme indoleamine 2,3-dioxygenase (IDO) (see below). Late in infection, and similarly in allergy, tolerogenic Treg cells which produce IL-10 and TGF-0 inhibit Th2 cells and prevent allergy to the fungus.
It has long been known that the ability of C. albicans to establish an infection involves multiple components of the fungus, but its ability to persist in host tissue might involve primarily the immunosuppressive property of a major cell wall glyco-protein, mannan (Nelson et al., 1991). Although epitopes of mannan exist endowed with the ability to induce protective antibodies to the fungus, mannan and oligosac-charide fragments of it could be potent inhibitors of cell-mediated immunity and appear to reproduce the immune deficiency in patients with the mucocutaneous form of candidiasis (Fischer et al., 1978). CMC, although encompassing a variety of clinical entities, has also been associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) (Peterson et al., 1998). Interestingly, in APECED, the mutated gene has been proposed to be involved in the ontogeny CD25+ Treg cells (Sakaguchi et al., 1996). In CMC, both anergy and active lym-phoproliferation and variable-delayed hypersensitivity to the fungus are indeed observed (Lilic, 2002). As already discussed, this has been associated with a defective type 1 cytokine production without obvious increase in type 2 cytokine production (namely IL-4 or IL-5). However, variable, either increased or not, levels of IL-10 have also been observed, a finding that may lead to the speculation that an inherent alteration in receptor-mediated signaling in response to fungal polysac-charide, may predispose patients with CMC to a dysfunctional induction of Treg, negatively affecting the capacity of the Th1-dependent clearance of the fungus and without the activation of Th2 cells.
Collectively, these observations suggest that the capacity of Treg cells to inhibit aspects of innate and adaptive immunity may be central to their regulatory activity in fungal infections. This may result in the generation of immune responses vigorous enough to provide adequate host defense, without necessarily eliminating the pathogen (which could limit immune memory) or causing an unacceptable level of host damage. In the last two decades the immunopathogenesis of fungal infections and associated diseases was explained primarily in terms of Th1/Th2 balance. While the pathogenetic role of either subset may still hold true, the reciprocal regulation of both subsets is apparently outdated. It appears that a combination of different types of Treg cells controls the Th1, as well as the Th2 inflammatory responses (Figure 1.1).
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