ICOS enhances follicular T helper responses and deteriorates the pathogenic process of liver in mice infected withSchistosoma japonicum

Abstract

23 Background: Humoral immune responses play an important role in mediating liver 24 granulomatous inflammation and fibrosis in schistosomiasis. Follicular helper T (Tfh) cells 25 have a central role in mediating humoral immune responses. Generation of Tfh cells depends 26 on inducible T cell costimulator (ICOS) signaling, but the underlying molecular mechanisms 27 are incompletely understood in pathogenesis of schistosomiasis. 28 Methodology/Principal Findings: We used a strain of ICOS-transgenic (Tg) mice to 29 test the degrees of liver granulomatous inflammation and fibrosis, the frequency of splenic 30 Tfh cells and soluble egg antigen-specific cytokine responses longitudinally in mice 31following Schistosoma japonicum (S. japonicum) infection. In comparison with that in 32 wide-type (WT) mice, significantly severer liver granulomatous inflammation and fibrosis 33 and higher mortality were observed in ICOS-Tg mice. Significantly higher frequency of 34 splenic Tfh cells was accompanied by significantly higher levels of Bcl-6 and CXCR5 35 expression in the livers of ICOS-Tg mice. Furthermore, significantly higher levels of 36 SEA-specific IL-4, IL-6, IL-10, IL-13, IL-17A, IL-21 and TGF-β1 responses, but lower 37 levels of IFN-responses were detected in ICOS-Tg mice, which were abrogated by 38 treatment with ICOS blockers in vitro. In addition, significantly higher levels of serum 39 anti-SEA IgG were detected in ICOS-Tg mice. 40 Conclusions/Significance: The ICOS-related signaling may promote the pathogenesis 41 of murine schistosomiasis by polarizing Tfh cells, which may be immune check points for the 42 prevention and intervention of schistosomiasis.43 3 3 Author summary 44 Granulomatous inflammation and fibrosis in the liver are the major pathogenic 45 characteristics of schistosomiasis. ICOS is crucial for the development of Tfh cells, which are 46 the key modulators of B cell activation and humoral immunity. However, the underlying 47 molecular mechanisms are incompletely understood in pathogenesis of schistosomiasis. Here, 48 our results showed that the ICOS over-expression would significantly induce severer liver 49 inflammation and fibrosis, higher frequency of splenic Tfh, higher levels of anti-SEA IgG as 50 well as imbalanced SEA-specific cytokine responses in ICOS-Tg mice. The findings 51 suggested that ICOS signaling may promote the pathogenesis of murine schistosoma-related 52 liver inflammation and fibrosis by polarizing Tfh cells. Potentially, ICOS signaling and Tfh 53 cells may be immune check points for the prevention and intervention of schistosomiasis. 54 55 4 4 Introduction 56 S. japonicum infection remains a problem for human health in developing countries. 57 During the pathogenesis of schistosomiasis, S. japonicum infection-related egg deposition can 58 recruit inflammatory infiltrates and cause granulomatous inflammation and fibrosis in the 59 liver [1,2]. More importantly, continual pathogenic process of inflammation and fibrosis in 60 the liver usually impairs its function, even leadin...