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Abstract
BackgroundParasitic helminths need to suppress the host immune system to establish chronic infections. Paradoxically, immunosuppression induced by the worm also benefits the host by limiting excessive inflammation and tissue damage, which remains the major cause leading to serious morbidity and mortality. Regulatory T cells (Tregs) are key immune regulators of this mutualism. The successive rise in Tregs during schistosome infection plays a critical role in immunoregulation. We and others previously showed that Schistosoma japonicum (S. japonicum) egg antigens (SEA) induce Tregs both in vitro and in vivo. In addition, we identified that SjHSP60 derived from SEA significantly induces Tregs in vivo and in vitro. However, the contribution of SjHSP60 in SEA to Treg induction and the related mechanisms of the Treg induction have not yet been identified.Methodology/Principal FindingsIn this study, we showed that S. japonicum stress protein HSP60 (SjHSP60) was constitutively and extensively expressed in eggs of S. japonicum. SjHSP60 specially induced Tregs in vivo and in vitro without inducing other CD4+ T sub-populations including Th1, Th2 and Th17 cells. Furthermore, we showed that the SjHSP60-depleted SEA almost lost the ability in vitro and displayed a significant impaired ability to induce Tregs in vivo. Finally, our study illustrated that the mechanisms of SjHSP60-mediated induction of Tregs are through both conversion of CD4+CD25- T cells into CD4+CD25+Foxp3+ Tregs and expansion of preexisting CD4+CD25+Foxp3+ Tregs in a TLR4-dependent manner.Conclusions/SignificanceCollectively, our findings identify SjHSP60 as a major parasitic contributor of Treg induction in S. japonicum egg antigens, which not only contributes to the better understanding of the mechanism of immunoregulation during helminth infection, but also suggests its potential as a therapeutic target for control of immunopathology, allergic and autoimmune diseases.
Highlights
In response to various pathogenic infections, the host immune system develops complex signaling networks to eliminate the invading pathogens
Our previous findings indicated that S. japonicum stress protein HSP60 (SjHSP60), a schistosomal stress protein highly expressed by parasites in response to stresses in the host, is a strong inducer of regulatory T cells (Tregs) in vitro and in vivo [19]
We showed that SjHSP60 is constitutively and extensively expressed in eggs of S. japonicum, which induces Tregs efficiently and
Summary
In response to various pathogenic infections (e.g., parasites), the host immune system develops complex signaling networks to eliminate the invading pathogens. Dampening excessive immune responses is beneficial for the host to limit tissue immunopathologic damage and survive the acute infection period. This mutualism between the pathogen and the host is one of the most important phenotypic plasticity and fitness consequences of chronic infection [1,2,3,4,5]. Previous reports including our own showed that schistosome egg antigens (SEA) induce Tregs in vitro and in vivo [14,15,16,17,18]. We identified that SjHSP60 from SEA significantly induces Tregs in vivo and in vitro [19]. The contribution of SjHSP60 in SEA to Treg induction and the related mechanisms of the Treg induction have not yet been identified
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