Over one-third of the world population is infected with parasitic helminths, Strongyloides ssp. accounting for approximately 30-100 million infected people. In this study, we employ the experimental system of murine Strongyloides ratti infection to investigate the interaction of this pathogenic nematode with its mammalian host. We provide a comprehensive kinetic description of the immune response to S. ratti infection that was reflected by induction of antigen-specific IgM and IgG1, mast cell activation and a Th2-like cytokine response. T cells derived from infected mice displayed an increased IL-3, IL-4, IL-5, IL-13 and IL-10 response to CD3-engagement in comparison with T cells derived from naïve mice. The IFN-gamma response to CD3-engagement that was well detectable in T cells derived from naïve mice, however, was suppressed in T cells derived from infected mice. Both, the induction of the S. ratti-specific Th2 response and the suppression of pro-inflammatory cytokines were transient and observed in strict correlation to the course of infection and the number of infective larvae used. Finally, comparing artificial infections induced by subcutaneous injection of larvae to natural infections, we observed similar antigen-specific T cell responses although the natural infection led to a significantly lower worm burden.

The quality of the adaptive immune response depends on the differentiation of distinct CD4(+) helper T cell subsets, and the magnitude of an immune response is controlled by CD4(+)Foxp3(+) regulatory T cells (Treg cells). However, how a tissue- and cell type-specific suppressor program of Treg cells is mechanistically orchestrated has remained largely unexplored. Through the use of Treg cell-specific gene targeting, we found that the suppression of allergic immune responses in the lungs mediated by T helper type 2 (TH2) cells was dependent on the activity of the protein kinase CK2. Genetic ablation of the β-subunit of CK2 specifically in Treg cells resulted in the proliferation of a hitherto-unexplored ILT3(+) Treg cell subpopulation that was unable to control the maturation of IRF4(+)PD-L2(+) dendritic cells required for the development of TH2 responses in vivo.

Accumulating evidence suggests that IL-9-mediated immunity plays a fundamental role in control of intestinal nematode infection. Here we report a different impact of Foxp3+ regulatory T cells (Treg) in nematode-induced evasion of IL-9-mediated immunity in BALB/c and C57BL/6 mice. Infection with Strongyloides ratti induced Treg expansion with similar kinetics and phenotype in both strains. Strikingly, Treg depletion reduced parasite burden selectively in BALB/c but not in C57BL/6 mice. Treg function was apparent in both strains as Treg depletion increased nematode-specific humoral and cellular Th2 response in BALB/c and C57BL/6 mice to the same extent. Improved resistance in Treg-depleted BALB/c mice was accompanied by increased production of IL-9 and accelerated degranulation of mast cells. In contrast, IL-9 production was not significantly elevated and kinetics of mast cell degranulation were unaffected by Treg depletion in C57BL/6 mice. By in vivo neutralization, we demonstrate that increased IL-9 production during the first days of infection caused accelerated mast cell degranulation and rapid expulsion of S. ratti adults from the small intestine of Treg-depleted BALB/c mice. In genetically mast cell-deficient (Cpa3-Cre) BALB/c mice, Treg depletion still resulted in increased IL-9 production but resistance to S. ratti infection was lost, suggesting that IL-9-driven mast cell activation mediated accelerated expulsion of S. ratti in Treg-depleted BALB/c mice. This IL-9-driven mast cell degranulation is a central mechanism of S. ratti expulsion in both, BALB/c and C57BL/6 mice, because IL-9 injection reduced and IL-9 neutralization increased parasite burden in the presence of Treg in both strains. Therefore our results suggest that Foxp3+ Treg suppress sufficient IL-9 production for subsequent mast cell degranulation during S. ratti infection in a non-redundant manner in BALB/c mice, whereas additional regulatory pathways are functional in Treg-depleted C57BL/6 mice.

Besides their central function in protein folding and transport within the cell, heat shock proteins (HSP) have been shown to modulate innate and adaptive immune response: (1) HSP mediate uptake and MHC presentation of HSP-associated peptides by antigen-presenting cells (APC). (2) HSP function as endogenous danger signals indicating cell stress and tissue damage to the immune system. (3) HSP bind pathogen-associated molecular pattern (PAMP) molecules and modulate PAMP-induced Toll-like receptor (TLR) signaling. Thus, HSP contribute to both, recognition of "danger" defined as uncontrolled tissue destruction and recognition of dangerous "nonself". In this review these different aspects of immune stimulation by HSP will be discussed.

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Activation of professional antigen-presenting cells (APC) is Activation of antigen-presenting cells (APC)2 such as dendritic cells (DC) and macrophages is a critical step in the initiation of innate as well as adaptive immune responses and is known to be induced by pathogen-associated molecular pattern (PAMP) molecules such as bacterial lipopolysaccharide (LPS) and other endotoxins. These molecules are recognized by pattern recognition receptors (PRR) like members of the conserved Toll-like receptor (TLR) family (1, 2). In the last years, several members of the heat shock protein (HSP) family including Hsp60 have been described to modulate APC functions and to stimulate immune responses in vitro and in vivo (3-6). Therefore, HSP have been suspected to function as endogenous danger signals to the immune system (4, 7-9). HSP are highly conserved and ubiquitously expressed proteins that are normally hidden within the cell and function as molecular chaperons of nascent or aberrantly folded proteins in different cellular compartments (10, 11). HSP are up-regulated and released from cells upon various cellular stresses and necrotic cell death (12, 13). Furthermore, stress-induced cell surface expression of HSP like Hsp60, which is normally localized within the mitochondria playing an essential role in the folding of imported mitochondrial proteins has been observed (14 -17). Extracellular Hsp60 has been shown to induce the maturation of human and murine DC and macrophages indicated by an up-regulation of co-stimulatory cell surface molecules and the production of the proinflammatory cytokines IL-1, and TNF␣ (7,18,19). Moreover, Hsp60 has been shown to enhance IFN␥ production in antigen-dependent T cell activation (4, 6), an effect that was mainly ascribed to the release of IL-12 by APC (20, 21). The receptors that have been proposed to be responsible for Hsp60-mediated immune effects are CD14 (18) and members of the TLR family, namely TLR4 (22, 23) and TLR2 (23,24). The receptor complex consisting of the glycosylphosphatidylinositol-anchored CD14 co-receptor and the TLR4 signaling receptor is known to mediate LPS signaling (25), whereas TLR2 is a receptor for bacterial lipoproteins and lipoteichoic acid (26 -28). The Hsp60 preparations, however, that have been used in earlier studies were expressed in Escherichia coli and, therefore, were likely to be contaminated with bacterial endotoxins. For this reason, it could not be excluded that the observed effects were due to contaminating bacterial structures, especially LPS, rather than the Hsp60 protein itself, although controls like heat sensitivity and polymyxine B insensitivity of Hsp60 versus LPS were included (8).Employing eukaryotic cell lines expressing the murine Hsp60 as a membrane-bound cell surface protein we have shown that Hsp60 enhances IFN␥ production in antigen-dependent T cell activation in an endotoxin-free environment, clearly demon-* The costs of publication of this article were defrayed in part by the payment of page charges. This article must ther...

In mammalians, toll-like receptors (TLR) signal-transduction pathways induce the expression of a variety of immune-response genes, including inflammatory cytokines. It is therefore plausible to assume that TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the substantia nigra in Parkinson disease (PD). Accordingly, recent data indicate that TLR4 is up-regulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in a mouse model of PD. Here, we wished to evaluate the role of TLR4 in the acute mouse MPTP model of PD: TLR4-deficient mice and wild-type littermates control mice were used for the acute administration way of MPTP or a corresponding volume of saline. We demonstrate that TLR4-deficient mice are less vulnerable to MPTP intoxication than wild-type mice and display a decreased number of Iba1+ and MHC II+ activated microglial cells after MPTP application, suggesting that the TLR4 pathway is involved in experimental PD.

The transmembrane protein CD83 has been initially described as a maturation marker for dendritic cells. Moreover, there is increasing evidence that CD83 also regulates B cell function, thymic T cell maturation, and peripheral T cell activation. Herein, we show that CD83 expression confers immunosuppressive function to CD4+ T cells. CD83 mRNA is differentially expressed in naturally occurring CD4+CD25+ regulatory T cells, and upon activation these cells rapidly express large amounts of surface CD83. Transduction of naive CD4+CD25− T cells with CD83 encoding retroviruses induces a regulatory phenotype in vitro, which is accompanied by the induction of Foxp3. Functional analysis of CD83-transduced T cells in vivo demonstrates that these CD83+Foxp3+ T cells are able to interfere with the effector phase of severe contact hypersensitivity reaction of the skin. Moreover, adoptive transfer of these cells prevents the paralysis associated with experimental autoimmune encephalomyelitis, suppresses proinflammatory cytokines IFN-γ and IL-17, and increases antiinflammatory IL-10 in recipient mice. Taken together, our data provide the first evidence that CD83 expression can contribute to the immunosuppressive function of CD4+ T cells in vivo.