Regulatory T cells (Treg) are vital in maintaining the homeostasis of immune reactions. In chronic infections, such as schistosomiasis, it remains unclear whether engagement of the TLR family is required to induce Treg activity. Thus, we performed in vivo studies using TLR2 -/-mice infected with Schistosoma mansoni and found elevated immunopathology, decreased egg burden and extended antigen-specific Th1 responses. Simultaneously, the population of Treg failed to expand. To evaluate the role of Treg during infection, we functionally inactivated CD4 + CD25 + T cells and observed that the resulting immunopathology mirrored that in TLR2 -/-mice. Egg burden was also reduced in anti-CD25-treated mice, indicating that without Treg eggs are more efficiently destroyed. In addition, antigen-specific T cells from both TLR2 -/-and anti-CD25-treated mice displayed an extended Th1 phase. Finally, adoptive transfer of schistosome-primed, but not naive CD4 + CD25 + T cells was able to resolve the immunopathology in TLR2 -/-recipients and interestingly, this amelioration was independent of TLR2 being present on the transferred Treg. We conclude that TLR2 is necessary for priming active Treg and their expansion during schistosomiasis.

Although several markers have been associated with the characterization of regulatory T cells (Tregs) and their function, no studies have investigated the dynamics of their phenotype during infection. Since the necessity of Tregs to control immunopathology has been demonstrated, we used the chronic helminth infection model Schistosoma mansoni to address the impact on the Treg gene repertoire. Before gene expression profiling, we first studied the localization and Ag-specific suppressive nature of classically defined Tregs during infection. The presence of Foxp3+ cells was predominantly found in the periphery of granulomas and isolated CD4+CD25hiFoxp3+ Tregs from infected mice and blocked IFN-γ and IL-10 cytokine secretion from infected CD4+CD25− effector T cells. Furthermore, the gene expression patterns of Tregs and effector T cells showed that 474 genes were significantly regulated during schistosomiasis. After k-means clustering, we identified genes exclusively regulated in all four populations, including Foxp3, CD103, GITR, OX40, and CTLA-4—classic Treg markers. During infection, however, several nonclassical genes were upregulated solely within the Treg population, such as Slpi, Gzmb, Mt1, Fabp5, Nfil3, Socs2, Gpr177, and Klrg1. Using RT-PCR, we confirmed aspects of the microarray data and also showed that the expression profile of Tregs from S. mansoni-infected mice is simultaneously unique and comparable with Tregs derived from other infections.

Chlamydia pneumoniae, an obligate intracellular bacterium, causes pneumonia in humans and mice. In this study, we show that GR1+/CD45+ polymorphonuclear neutrophils (PMN) surprisingly increase the bacterial load of C. pneumoniae in vivo. Upon intranasal infection of wild-type mice, the lung weight is increased; the cytokines TNF, IL-12p40, and IFN-γ, as well as the chemokines keratinocyte-derived chemokine, MCP-1, and MIP-2 are secreted; and GR1+/CD45+ PMN are recruited into lungs 3 days postinfection. In contrast, in infected MyD88-deficient mice, which lack a key adaptor molecule in the signaling cascade of TLRs and IL-1R family members, the increase of the lung weight is attenuated, and from the analyzed cyto- and chemokines, only IL-12p40 is detectable. Upon infection, almost no influx of inflammatory cells into lungs of MyD88-deficient mice can be observed. Six days postinfection, however, MyD88-deficient mice were able to produce TNF, IFN-γ, keratinocyte-derived chemokine, and MCP-1 in amounts similar to wild-type mice, but failed to secrete IL-12p40 and MIP-2. At this time point, the infection increased the lung weight to a level similar to wild-type mice. Curiously, the chlamydial burden in MyD88-deficient mice 3 days postinfection is lower than in wild-type mice, a finding that can be reproduced in wild-type mice by depletion of GR1+ cells. In analyzing how PMN influence the chlamydial burden in vivo, we find that PMN are infected and enhance the replication of C. pneumoniae in epithelial cells. Thus, the lower chlamydial burden in MyD88-deficient mice can be explained by the failure to recruit PMN.

Heat shock protein 60 (HSP60) from Chlamydia pneumoniae was described to trigger in vitro inflammatory and cytokine responses including TNF and IL-12p40. Although it can be found in atherosclerotic plaques of patients, the stimulatory potential of chlamydial and other HSP60 in vivo is unclear. We now report that chlamydial HSP60 fails to induce TNF expression in vivo, and significant serum levels of IL-12p40 are only found upon intraperitoneal injection of high doses of HSP60 or after intravenous application. Upon purification of chlamydial HSP60 with polymyxin B-agarose columns, its ability to induce TNF secretion in vitro is much reduced. However, purified chlamydial HSP60 causes increased serum levels of the CXC chemokines KC and MIP2 in vivo, as well as a strong accumulation of polymorphonuclear neutrophils (PMN) in the peritoneal cavity upon intraperitoneal challenge. With respect to PMN accumulation, chlamydial HSP60 is more potent than endotoxin or the CpG oligonucleotide 1668. The responses observed are completely abolished in Toll-like receptor (TLR)2/4-double-deficient mice, while single-deficient mice respond almost normally. Furthermore, KC induction and PMN accumulation are largely dependent on MyD88. In conclusion, HSP60 from C. pneumoniae triggers inflammatory responses in vivo that differ from responses induced by endotoxin or CpG oligonucleotides and are dependent on TLR2 and 4.

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Early exposure to immune stimuli, including maternal infection during the perinatal period, is increasingly recognized to affect immune predisposition during later life. This includes exposure to not only viral and bacterial infection but also parasitic helminths which remain widespread. Noted effects of helminth infection, including altered incidence of atopic inflammation and vaccine responsiveness, support further research into the impact these infections have for skewing immune responses. At the same time, despite a sea of recommendations, clear phenotypic and mechanistic understandings of how environmental perturbations in pregnancy and nursing modify immune predisposition and allergy in offspring remain unrefined. Schistosomes, as strong inducers of type 2 immunity embedded in a rich network of regulatory processes, possess strong abilities to shift inflammatory and allergic diseases in infected hosts, for example by generating feedback loops that impair T cell responses to heterologous antigens. Based on the current literature on schistosomiasis, we explore in this review how maternal schistosome infection could drive changes in immune system development of offspring and how this may lead to identifying factors involved in altering responses to vaccination as well as manifestations of immune disorders including allergy.

Schistosome infections are renowned for their ability to induce regulatory networks such as regulatory T cells (Treg) that control immune responses against homologous and heterologous antigens such as allergies. However, in the case of co-infections with hepatitis C virus (HCV), schistosomes accentuate disease progression and we hypothesized that expanding schistosome-induced Treg populations change their phenotype and could thereby suppress beneficial anti-HCV responses. We therefore analysed effector T cells and n/iTreg subsets applying the markers Granzyme B (GrzB) and Helios in Egyptian cohorts of HCV mono-infected (HCV), schistosome-co-infected (Sm/HCV) and infection-free individuals. Interestingly, viral load and liver transaminases were significantly elevated in Sm/HCV individuals when compared to HCV patients. Moreover, overall Treg frequencies and Helios(pos) Treg were not elevated in Sm/HCV individuals, but frequencies of GrzB(+) Treg were significantly increased. Simultaneously, GrzB(+) CD8(+) T cells were not suppressed in co-infected individuals. This study demonstrates that in Sm/HCV co-infected cohorts, liver disease is aggravated with enhanced virus replication and Treg do not expand but rather change their phenotype with GrzB possibly being a more reliable marker than Helios for iTreg. Therefore, curing concurrent schistosome disease could be an important prerequisite for successful HCV treatment as co-infected individuals respond poorly to interferon therapy.