Blockade of PD-1 Signaling Enhances Th2 Cell Responses and Aggravates Liver Immunopathology in Mice with Schistosomiasis japonica

Abstract

BackgroundMore than 220 million people worldwide are chronically infected with schistosomes, causing severe disease or even death. The major pathological damage occurring in schistosomiasis is attributable to the granulomatous inflammatory response and liver fibrosis induced by schistosome eggs. The inflammatory response is tightly controlled and parallels immunosuppressive regulation, constantly maintaining immune homeostasis and limiting excessive immunopathologic damage in important host organs. It is well known that the activation of programmed death 1 (PD-1) signaling causes a significant suppression of T cell function. However, the roles of PD-1 signaling in modulating CD4+ T cell responses and immunopathology during schistosome infection, have yet to be defined.Methodology/Principal FindingsHere, we show that PD-1 is upregulated in CD4+ T cells in Schistosoma japonicum (S. japonicum)-infected patients. We also show the upregulation of PD-1 expression in CD4+ T cells in the spleens, mesenteric lymph nodes, and livers of mice with S. japonicum infection. Finally, we found that the blockade of PD-1 signaling enhanced CD4+ T helper 2 (Th2) cell responses and led to more severe liver immunopathology in mice with S. japonicum infection, without a reduction of egg production or deposition in the host liver.Conclusions/SignificanceOverall, our study suggests that PD-1 signaling is specifically induced to control Th2-associated inflammatory responses during schistosome infection and is beneficial to the development of PD-1-based control of liver immunopathology.

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

“…Strikingly, PD-1 + T H 17 cells are present in pulmonary fibrosis of distinct etiologies [chronic antigenic stimulation from microbial antigens (for example, sarcoidosis) (32), genetic alterations in the Src homology 2 domain–containing phosphotyrosine phosphatase-2 (Shp2) signaling pathway (for example, IPF) (33), or bleomycin- induced pulmonary fibrosis], suggesting that the PD-1/STAT3/T H 17 pathway may represent a point of immunologic convergence resulting in organ fibrosis. The presence of PD-1 + CD4 + and CD8 + T cell up-regulation in liver and skin fibrosis has also been reported (34). …”

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model

“…(14,20,21) Specific T cells become exhausted within the chronic inflammatory area of infected organs, thus contributing over the long term to the escape of viruses, parasites, or tumor cells from immune attack. (10,(22)(23)(24) Several key surface molecules, such as PDCD1, LAG3, and CTLA4, which are associated with T-cell exhaustion and the blocking of which may recover the T-cell function, have been recognized and are usually defined as "immunocheckpoints" or more simply "checkpoints." (11,25) In the present study, our results demonstrated that TIGIT plays a critical role in parasite immune escape by negatively controlling antiparasite T-cell immunity; they showed that blocking TIGIT decreased E. multilocularis growth in experimental animals while restoring T-cell immune effector function and thus highly suggested that blocking TIGIT could treat AE in future clinical practice.…”

B cells induced by Schistosoma japonicum infection display diverse regulatory phenotypes and modulate CD4+ T cell response

“…Studies in mice with schistosome and Litomosoides sigmodontis infection have indicated that Th2 hypo-responsiveness is not related to PD-1 and PD-L1 interaction [22,57,58]. However, other studies have suggested that PD-1 is necessary for the Th2 hyporesponsiveness during schistosome infection [19,59]. Our findings from the PD-L1 blocking experiment in vivo were consistent with the latter, as we observed that PD-L1 blocking not only enhanced the expression of IL-4 and Bcl6 in splenic CD4 + T cells but also increased the expression of Th2 transcription factor Gata3.…”