Heat Shock Protein 60 in Eggs Specifically Induces Tregs and Reduces Liver Immunopathology in Mice with Schistosomiasis Japonica

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.

SjHSP60 induces CD4+CD25+Foxp3+ Tregs via TLR4‐Mal‐drived production of TGF‐β in macrophages

“…Similarly, our previous study demonstrated that APCs, for example, Mφ or DC, are necessary in SjHSP60, a major S. japonicum egg antigen, mediated conversion of CD4 + CD25 À T cells into Tregs. 30 Here, our result further showed that in contrast to lipopolysaccharide-stimulated Mφ (LPS-Mφ), SjHSP60-treated Mφ (SjHSP60-Mφ) retained an immature morphology with a more rounded shape (Supplementary figure 1c). FCM (flow cytometry) analysis revealed that less profoundly increased expression of MHC class II and co-stimulatory molecules (CD40, CD80 and CD86), but more significant upregulation of co-inhibitory molecule (programmed death ligand 1, PD-1/B7-H1) on SjHSP60-Mφ (Supplementary figure 1d).…”

“…[25][26][27][28] Our previous studies also have shown that the S. japonicum stress protein HSP60 (heat shock protein 60, SjHSP60) and a SjHSP60derived peptide SJMHE1 significantly induce immunosuppressive Tregs both in vitro and in vivo through TLR on APCs (Mφ or dendritic cells, DCs) by inducing higher levels of TGF-b. 29,30 However, whether and how schistosome antigens manipulate TLR signaling to promote TGF-b production in APCs and thereby induce Tregs remains to be resolved.…”

Interleukin‐9 blockage reduces early hepatic granuloma formation and fibrosis during Schistosoma japonicum infection in mice

“…The reason is that regulatory T cells play an important repressor role in the down‐regulation of pathological immune responses at this stage. Previous studies have shown that regulatory T cells and their functional factor IL‐10 could prevent the response of Th1, Th2 and Th17 . Hence, the schistosome‐induced hepatic pathology is regulated by multiple cytokines.…”

“…Previous studies have shown that regulatory T cells and their functional factor IL-10 could prevent the response of Th1, Th2 and Th17. 18,19 Hence, the schistosome-induced hepatic pathology is regulated by multiple cytokines.…”

Identification of a TNF-α inducer MIC3 originating from the microneme of non-cystogenic, virulent Toxoplasma gondii

“…The IP of MIC3 from ESAs was performed as described previously with some modification59. For a single IP, 20 μl mouse monoclonal antibody to T. gondii MIC3 (anti-MIC3 mAb, GeneTex) was incubated with 200 μl protein G-agarose suspension (Sigma-Aldrich, St. Louis, MO, USA) at 4 °C for 3 h. Next, anti-MIC3 mAb conjugated to the protein G-agarose suspension was collected by centrifugation, mixed with ESAs (200 μg) and incubated with mixing at 4 °C for 3 h. Finally, the protein G-agarose was removed by centrifugation.…”