Tuning the Adaptive Immune Responses The Instructive Role of DC

As DC are equipped with several TLR, they are the main connectors of the innate and adaptive immune systems. DC are bone marrow-derived cells of both lym-phoid and myeloid stem cell origins that populate all lymphoid organs, as well as nearly all nonlymphoid tissues and organs. The dual activation/tolerization function of DC is mediated by their capacity to change the context of antigen presentation and to communicate to T cells the nature of the antigens they are presenting. This process exemplifies the importance of TLR not only in direct early immune responses, but also in activation of adaptive immunity. The DC system consists of a network of different subpopulations (Romani & Puccetti, 2006a). The ability of a given DC subset to respond with flexible activating programs to the different stimuli, as well as the ability of different subsets to convert into each others confers unexpected plasticity to the DC system. DC are uniquely adept at decoding the fungus-associated information and translating it in qualitatively different adaptive T-cell immune responses (Romani & Puccetti, 2006a). PRR (such as CR, FcR, C-type lectins (such as DC-SIGN and dectin-1), MR, and TLR determine the functional plasticity of DC in response to fungi and contribute to the discriminative recognition of the different fungal morphotypes. DC (both human and murine) are now known to recognize and internalize a number of fungi, including A. fumigatus, C. albicans, C. neoformans, H. capsulatum, Malassezia furfur, and Saccharomyces cerevisiae and fungi and fungal products may affect DC functioning as well (Romani & Puccetti, 2006a; Buentke & Scheynius, 2003). DC are also known to cross-present exogenous fungal antigens through uptake of apoptotic macrophage-associated fungal antigens (Lin et al., 2005). Profiling gene expression on DC by microarray technologies has revealed that both shared response and a pathogen-specific gene expression program were induced upon the exposure to bacteria, viruses and fungi. Additional studies with S. cerevisiae have shown that recombinant yeast could represent an effective vaccine for the generation of broad-based cellular immune responses. It seems, therefore, that DC are uniquely able at decoding the fungus-associated information at the host-fungus interface. Candida and Aspergillus proved to be useful pathogen models to dissect events occurring at the fungus-DC interface. Murine and human DC internalize Candida yeasts, Aspergillus conidia and hyphae of both. The uptake of the different fungal elements occurred through different receptors and forms of phagocytosis. Transmission electronic microscopy indicated that internalization of yeasts and conidia occurred predominantly by coiling phagocytosis, characterized by the presence of overlapping bilateral pseudopods, which led to a pseudopodal stack before transforming into a phagosome wall. In contrast, entry of hyphae occurred by a more conventional zipper-type phagocytosis, characterized by the presence of symmetrical pseudo-pods which strictly followed the contour of the hyphae before fusion. Recognition and internalization of unopsonized yeasts and conidia occurred through the engagement of MR of different sugar specificity, DC-SIGN, dectin-1, and partly, CR3 (Claudia et al., 2002; Mansour et al., 2006). In contrast, entry of hyphae occurred by a more conventional, zipper-type phagocytosis and involved the cooperative action of FcyR II and III and CR3. Phagocytosis does not require TLR/MyD88. Consistent with the findings that signals from protein kinase C (PKC) and/or protein tyrosine kinases are required for phagocytosis in a variety of systems, the PKC inhibitor staurosporine was required for CR- and FcyR-mediated phagocytosis, while FcyR- and, to a lesser extent, MR-mediated phagocytosis required signaling through protein tyrosine kinases (Claudia et al., 2002). The results are consistent with the view that fungi have exploited common pathways for entry into DC, which may include a lectin-like pathway for unicellular forms and opsono-dependent pathways for filamentous forms.

The engagement of distinct receptors by distinct fungal morphotypes translates into downstream signaling events, ultimately regulating cytokine production and costimulation, an event greatly influenced by fungal opsonins, such as MBL, C3, and/or antibodies (Romani et al., 2004; Romani et al., 2002). Entry through MR and dectin-1 resulted in the production of pro-inflammatory cytokines, including IL-12, upregulation of costimulatory molecules and histocompatibility Class II antigens. IL-12 production by DC required the MyD88 pathway with the implication of distinct TLR. These events were all suppressed upon entry through CR3. In contrast, coligation of CR3 with FcyR, as in the phagocytosis of hyphae, resulted in the production of IL-4/IL-10 and upregulation of costimulatory molecules and histocompatibility Class II antigens. The production of IL-10 was largely MyD88-independent. Therefore, TLR collaborate with other innate immune receptors in the activation of DC against fungi through MyD88-dependent and MyD88-independent pathways (Romani & Puccetti, 2006a).

A remarkable and important feature of DC is their capacity to produce IL-10 in response to fungi. These IL-10-producing DC activate CD4+ CD25+ Treg cells that are essential components of antifungal resistance (see below). Thus, by subverting the morphotype-specific program of activation of DC, opsonins, antibodies, and other environmental factors may qualitatively affect DC functioning and Th/Treg selection in vivo, ultimately impacting on fungal virulence. In this scenario, the qualitative development of the Th cell response to a fungus may not primarily depend on the nature of the fungal form being phagocytosed and presented. Rather, the nature of the cell response is strongly affected by the type of cell signaling initiated by the ligand-receptor interaction in DC. For Candida, the paradigm would predict that dimorphism per se can no longer be considered as the single most important factor in determining commensalism versus infection, nor can specific forms of the fungus be regarded as absolutely indicative of saprophytism or infection at a given site. The selective exploitation of receptor-mediated entry of fungi into DC could explain the full range of host immune-parasite relationships, including saprophytism and infection. Importantly, as both fungal morphotypes, but particularly hyphae, activate gut DC for the local induction of Treg cells and because the morphogenesis of C. albicans is activated in vivo by a wide range of signals, it appears that the discriminative response towards Treg cell function is of potential teleological meaning. It could indeed allow for fungal persistence in the absence of the pathological consequences of an exaggerated immunity and possible autoimmunity, a condition which represents the very essence of fungal commensal-ism. Therefore, in addition to the induction of phase-specific products enhancing fungal survival within the host, transition to the hyphal phase of the fungus could implicate the induction of immunoregulatory events that will benefit the host.

Fungus-pulsed DC translated fungus-associated information to Th1, Th2, and Treg cells, in vitro and in vivo (Romani & Puccetti, 2006a). In vivo, the balance among the different DC subsets determined whether protective or nonprotective antifungal cell-mediated immune responses developed. Fungus-pulsed DC activated different CD4+ Th cells upon adoptive transfer in a murine model of allogeneic bone marrow transplantation (Bozza et al., 2005; Romani et al., 2006). The ability of fungus-pulsed DC to prime for Th1 and Th2 cell activation upon adoptive transfer in vivo correlated with the occurrence of resistance and susceptibility to the infections. Recent data have shown that the infusion of fungus-pulsed

DC of the different subsets accelerated the recovery of peripheral antifungal Th1 immunity and increased resistance to fungal infections in a murine model of allogeneic bone marrow transplantation (Romani et al., 2006). However, only the co-infusion of DC of both subsets resulted in: (i) induction of T reg cells capable of a fine control over the inflammatory pathology; (ii) tolerization toward alloanti-gens; and (iii) diversion from alloantigen-specific to antigen-specific Tcell responses in the presence of donor T lymphocytes. Thus, the adoptive transfer of DC may restore antifungal immunocompetence in hematopoietic transplantation by contributing to the educational program of T cells through the combined action of activating and tolerizing DC. These results, along with the finding that fungus- pulsed DC could reverse T-cells anergy of patients with fungal diseases (Romani & Puccetti, 2006a), may suggest the utility of DC for fungal vaccines and vaccination (Bozza et al., 2004; Lam et al., 2005).

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