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

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a pivotal role in limiting immunopathological damage to host organs after schistosome infection. Transforming growth factor-β (TGF-β) is an essential factor for the periphery conversion of CD4+ CD25- T cells into CD4+ CD25+ Foxp3+ Tregs by inducing the key transcription factor Foxp3. Antigen presenting cells (APCs), which highly express TGF-β, are involved in parasite antigen-induced Treg conversion in peripheral. However, the mechanisms underlying high TGF-β induction in APCs by parasite antigens remain to be clarified during schistosome infection. Here, we demonstrated that Schistosoma japonicum stress protein, heat shock protein 60 (SjHSP60), promoted TGF-β production in macrophages (Mφ). Furthermore, we showed that activation of TLR4-Mal (MyD88 adaptor-like protein) signaling by SjHSP60 is necessary for induction of TGF-β expression in Mφ, which subsequently promoted Treg induction. Our results not only demonstrate a novel mechanism of TGF-β production in Mφ for inducing Tregs in mice with schistosomiasis, but also allude to the possibility of targeting parasite stress protein for potential therapeutics.