The development of type 1 diabetes involves a complex interaction between pancreatic beta-cells and cells of both the innate and adaptive immune systems. Analyses of the interactions between natural killer (NK) cells, NKT cells, different dendritic cell populations and T cells have highlighted how these different cell populations can influence the onset of autoimmunity. There is evidence that infection can have either a potentiating or inhibitory role in the development of type 1 diabetes. Interactions between pathogens and cells of the innate immune system, and how this can influence whether T cell activation or tolerance occurs, have been under close scrutiny in recent years. This Review focuses on the nature of this crosstalk between the innate and the adaptive immune responses and how pathogens influence the process.

Infection with Schistosoma mansoni (S. mansoni) or exposure to eggs from this helminth inhibits the development of type 1 diabetes in NOD mice. In this study we show that soluble extracts of S. mansoni worm or egg completely prevent onset of type 1 diabetes in these mice but only if injection is started at 4 weeks of age. T cells from diabetes-protected mice make IL-10 in recall responses to parasite antigens. These cells are furthermore impaired in their ability to transfer diabetes to NOD-SCID recipients. Bone marrow dendritic cells derived from NOD mice are found to make more IL-10 and less IL-12 following culture with S. mansoni soluble egg antigens in conjunction with lipopolysaccharides. NOD mice are deficient in NKT cells. Soluble worm and egg antigens increase the numbers of V § 14i NKT cells in NOD mice. These effects of schistosome antigens on the innate immune system provide a mechanism for their ability to prevent type 1 diabetes in NOD mice.

Schistosoma mansoni soluble egg antigens (SEA) profoundly regulate the infected host's immune system. We previously showed that SEA prevents type 1 diabetes in NOD mice and that splenocytes from SEA-treated mice have reduced ability to transfer diabetes to NOD.scid recipients. To further characterize the mechanism of diabetes prevention we examined the cell types involved and showed that CD251 T-cell depletion of splenocytes from SEA-treated donors restored their ability to transfer diabetes. Furthermore, SEA treatment increased the number and proportional representation of IntroductionParasitic helminths like Schistosoma mansoni have co-evolved with the immune systems of their mammalian hosts and have developed many strategies to suppress host responses. Intravenous egg deposition by female worms is accompanied by Th2 skewing of the host's immune system, which has been linked to the induction of DC with a suppressive phenotype and alternatively activated macrophages (MF) [1]. Although in vitro parasite-conditioned DC have been shown to retain an immature phenotype and have been shown to mediate an in vivo Th2 response indicative of parasite-mediated effects [2], most studies failed to identify clear phenotypic changes in DC. We and others have shown that after exposure to S. mansoni soluble egg antigens (SEA), DC have a reduced ability to secrete inflammatory mediators in response to TLR stimulation providing further evidence of SEA-mediated effects in DC [3][4][5][6]. Foxp3 1 Treg are important in regulating immune responses to helminth infections [7][8][9][10] and in preventing autoimmunity [11].In particular, the importance of Treg during the egg deposition phase of S. mansoni infection has been shown, with a demonstrated role in suppressing Th1 pathology while permitting a contained Th2 response [8][9][10]. However, links uniting the effect of SEA on DC with Treg functional effects have not so far been described.In the NOD mouse model of autoimmune type 1 diabetes we have shown that exposure of mice to either live S. mansoni infection or parasite-derived soluble antigen confers permanent protection against diabetes [3]. Increase in the frequency and activation of Foxp3 1 Treg has been shown to prevent diabetes in à These authors contributed equally to this work. (Fig. 1D). There was no change in the expression of IL-27p28 (data not shown). As not all TGF-b transcripts lead to biologically active protein, we also assessed the expression of PAI-1 [21], which can be induced by TGF-b signaling through Smads, and found that it was also increased in response to SEA (Fig. 1D). CD25À from SEA-treated mice at 75% and data not shown). All together these data suggest different mechanisms of protection between SEA and SWA and a possible role for Treg in diabetes prevention in SEA-treated NOD mice but not SWA-treated NOD mice. As depletion of Treg in vivo also caused the development of other forms of autoimmunity (e.g. colitis and thyroiditis) we turned to in vitro systems to model the early events favoring the prote...

Regulatory T cells (Tregs) have been implicated as key players in immune tolerance as well as suppression of antitumor responses. The chemotherapeutic alkylating agent cyclophosphamide (CY) is widely used in the treatment of tumors and some autoimmune conditions. Although previous data has demonstrated that Tregs may be preferentially affected by CY, its relevance in promoting autoimmune conditions has not been addressed. The nonobese diabetic mouse spontaneously develops type-1 diabetes (T1D). We demonstrate in this study that CY targets CD4+CD25+Foxp3+ Tregs in vivo. CD4+CD25+ T cells isolated from CY-treated mice display reduced suppressive activity in vitro and increased expression of apoptotic markers. Although Treg numbers rapidly recovered to pretreatment levels in the peripheral lymphoid tissues, Tregs failed to recover proportionally within pancreatic infiltrates. T1D progression was effectively prevented by adoptive transfer of a small number of islet Ag-specific CD4+CD25+ Tregs to CY-treated recipients. Prevention of T1D was associated with reduced T cell activation and higher Treg proportions in the pancreas. We conclude that acceleration of T1D by CY is associated with a reduction in CD4+CD25+Foxp3+ Tregs and can be prevented by transfer of CD4+CD25+ Tregs.

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