TLR2 Directing PD-L2 Expression Inhibit T Cells Response in Schistosoma japonicum Infection

Gao, Yanan; Chen, Lin; Hou, Min; Chen, Yingying; Ji, Minjun; Wu, Haiwei; Wu, Guan-Ling

doi:10.1371/journal.pone.0082480

Cited by 25 publications

(25 citation statements)

References 41 publications

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“…To our knowledge, the present study is the first to report a significantly higher expression of PD-1 in CD4 + T cells from chronic schistosomiasis patients. In consistence with previous report [19], we also observed a gradual increase in PD-1 expression in CD4 + T cells in vivo . Additionally, both splenic and mesenteric CD4 + T cells had a high expression level of PD-1, even 8 weeks post-infection.…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies have demonstrated that along with T cell suppression during schistosomal infection, the expression of PD-L1 and PD-L2 are selectively up-regulated in macrophages and dendritic cells respectively [18,19], suggesting critical roles for both PD-L1 and PD-L2 in regulating T cell responses during schistosomal infection. However, the role of PD-L1/L2 in the regulation of CD4 + T cell responses and egg-induced immunopathology during schistosomal infections have not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, numerous studies have shown that exploiting the PD-1 pathway may be of interest for the treatment of chronic viral infections, cancers and autoimmune diseases [12–14]. PD-1 ligand 1 and 2 (PD-L1/L2) have been shown to be significantly upregulated in macrophages and dendritic cells during schistosome infection, suggesting their involvement in T cell anergy [18,19]. However, very little is known about the regulation of PD-1 in CD4 + T cells or the impact of its signaling on the development of CD4 + T cell responses and egg-induced immunopathology during schistosome infections.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Zhou

Jin

et al. 2016

PLoS Negl Trop Dis

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhou

Jin

et al. 2016

PLoS Negl Trop Dis

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“…Supporting this idea, Guasconi et al [19] demonstrated using in vitro experimental settings that the blocking of PD-L2 in co-cultures of F. hepatica -ES-treated macrophages with anti-CD3-stimulated CD4+ T cells increases IFN-γ and decreases IL-10 production, without modifying IL-13 production. Similar results were observed by blocking PD-L2 in the co-cultures of bone marrow-derived dendritic cells (DC) stimulated with Schistosoma mansoni soluble egg antigens (ESA) and CD4+ T cells, where a significant rise in IFN-γ was observed [22]. …”

Section: Discussionsupporting

confidence: 60%

PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

et al. 2016

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Macrophage plasticity is critical for controlling inflammation including those produced by helminth infections, where alternatively activated macrophages (AAM) are accumulated in tissues. AAM expressing the co-inhibitory molecule programmed death ligand 2 (PD-L2), which is capable of binding programmed death 1 (PD-1) expressed on activated T cells, have been demonstrated in different parasitic infections. However, the role of PD-L2 during F. hepatica infection has not yet been explored. We observed that F. hepatica infection or a F. hepatica total extract (TE) injection increased the expression of PD-L2 on peritoneal macrophages. In addition, the absence of PD-L2 expression correlated with an increase in susceptibility to F. hepatica infection, as evidenced by the shorter survival and increased liver damage observed in PD-L2 deficient (KO) mice. We assessed the contribution of the PD-L2 pathway to Th2 polarization during this infection, and found that the absence of PD-L2 caused a diminished Th2 type cytokine production by TE stimulated splenocytes from PD-L2 KO infected compared with WT mice. Besides, splenocytes and intrahepatic leukocytes from infected PD-L2 KO mice showed higher levels of IFN-γ than those from WT mice. Arginase expression and activity and IL-10 production were reduced in macrophages from PD-L2 KO mice compared to those from WT mice, revealing a strong correlation between PD-L2 expression and AAM polarization. Taken together, our data indicate that PD-L2 expression in macrophages is critical for AAM induction and the maintenance of an optimal balance between the Th1- and Th2-type immune responses to assure host survival during F. hepatica infection.

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“…LTA molecules have been shown to signal via TLR2, which is expressed on a wide variety of cells, including macrophages and dendritic cells [3; 41]. TLR2 signaling has been shown to negatively regulate T-cell activation and co-stimulation via expression of the ligands PDL1 and PDL2 [12; 45]. To examine whether SELTA mediates reduction in IL17A expressing T-cells and pelvic tactile allodynia in EAP mice through this pathway we performed flow cytometry on single cell suspensions of prostate tissues in EAP mice following 7 days treatment with SELTA.…”

Section: Resultsmentioning

confidence: 99%

Commensal bacterial modulation of the host immune response to ameliorate pain in a murine model of chronic prostatitis

Murphy

Schaeffer²,

Done³

et al. 2017

Pain

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The human commensal microflora plays an essential role in modulating the immune response to control homeostasis. Staphylococcus epidermidis, a commensal bacteria most commonly associated with the skin exerts such effects locally, modulating local immune responses during inflammation and preventing superinfection by pathogens such as Staphylococcus aureus. While the prostate is considered by many to be sterile, multiple investigations have shown that small numbers of gram-positive bacterial species such as S. epidermidis can be isolated from the expressed prostatic secretions (EPS) of both healthy and diseased men. Chronic pelvic pain syndrome (CPPS) is a complex syndrome with symptoms including pain and lower urinary tract dysfunction (LUTs). It has an unknown etiology and limited effective treatments but is associated with modulation of prostate immune responses. CPPS can be modeled using murine experimental prostatitis (EAP) where CD4+ve IL17A+ve T-cells have been shown to play a critical role in disease orchestration and development of pelvic tactile allodynia. Here we report that intra-urethral instillation of a specific S. epidermidis strain (designated NPI (non pain-inducing)), isolated from the EPS of a healthy human male, into EAP treated mice reduced the pelvic tactile allodynia responses and the increased CD4+ve IL17A+ve T-cell numbers associated with EAP. Furthermore, a cell wall constituent of NPI, lipotechoic acid (LTA), specifically recapitulates these effects and mediates increased expression of CTLA4-like ligands PDL1 and PDL2 on prostatic CD11b+ve antigen presenting cells. These results identify a new potential therapeutic role for commensal S. epidermidis NPI LTA in the treatment of prostatitis-associated pain.

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TLR2 Directing PD-L2 Expression Inhibit T Cells Response in Schistosoma japonicum Infection

Cited by 25 publications

References 41 publications

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

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

PD-L2 negatively regulates Th1-mediated immunopathology during Fasciola hepatica infection

Commensal bacterial modulation of the host immune response to ameliorate pain in a murine model of chronic prostatitis

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