Association of TRAIL receptor with phosphatase SHP-1 enables repressing T cell receptor signaling and T cell activation through inactivating Lck.

BACKGROUND: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation. METHODS: Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells. RESULTS: TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation. CONCLUSIONS: TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.

Rituximab induction and reinduction in granulomatosis with polyangiitis and microscopic polyangiitis: A retrospective multicenter study in Taiwan.

OBJECTIVES: This study aimed to investigate the clinical outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) under rituximab induction and reinduction therapy in Taiwan. METHODS: We performed a retrospective study in patients with GPA or MPA receiving rituximab therapy from August 2008 to July 2020 in seven medical centers in Taiwan. The clinical characteristics and outcomes of these patients were analyzed. RESULTS: In total, 53 patients (18 with GPA and 35 with MPA) were included. Kidney involvement (82.9% vs. 22.2%, p < .001) and initial creatinine (3.25 ± 2.37 vs. 1.07 ± 0.82, p < .001) were significantly higher in MPA. Within 24 weeks after the first course of rituximab, there were seven deaths (five due to infection and two due to active disease) in patients with MPA (7/35, 20%) compared to 0 in patients with GPA. Of 33 patients receiving rituximab for kidney involvement, 23 survived and were free from renal replacement therapy at 24 weeks. Their chronic kidney disease (CKD) stages improved in 2 but progressed in 7, while 24 had stable CKD stages. Death or end-stage renal disease (ESRD) was associated with infection and higher initial creatinine. Reinduction therapy for relapse was required in 18 (39.1%) of 46 survivors, which was associated with anti-proteinase 3 (PR3) positive (odds ratio 3.667, p = .049) and younger age with a cutoff of 49.4 (AUC = 0.679, p = .030, sensitivity = 66.67%, specificity = 75%). CONCLUSION: Significant mortality occurred after rituximab induction, especially in patients with MPA. In survivors, age younger than 50 and anti-PR3 positive were associated with the risk of relapse requiring reinduction.

Rheumatic manifestations of hepatitis C virus infection are associated with autoantibodies but not viremia.

BACKGROUND: To investigate the associations between extrahepatic manifestations, autoantibodies, and viremia in patients with hepatitis C virus (HCV) infection. METHODS: This cross-sectional study recruited patients with HCV infection from the outpatient department of a tertiary medical center in Northern Taiwan between January 2017 and August 2019. Autoantibody profiles and the clinical parameters of HCV infection were evaluated using laboratory tests, and a questionnaire was used to record extrahepatic manifestations. HCV infection status, including inactive HCV infection, active hepatitis, and cirrhosis, was defined according to abdominal ultrasonography findings and alanine transaminase levels. RESULTS: A total of 77 patients with HCV were recruited, with 19.5% and 16.9% of patients, respectively, presenting with arthritis and dry eyes. Autoantibody screening revealed rheumatoid factor (RF), antinuclear antibody (ANA), anti-Ro antibody, and anti-La antibody positivity in 20.8%, 23.4%, 13.0%, and 2.6% of the patients, respectively. The presence of RF was associated with arthritis, whereas the presence of ANA was associated with dry eyes but not dry mouth. Active hepatitis and HCV-related cirrhosis were associated with viremia, but not autoantibody profiles. CONCLUSION: In this single-center study, the prevalence of extrahepatic manifestations and autoantibodies did not differ in patients stratified by the HCV infection status. Rheumatic manifestations were associated with the presence of autoantibodies but not with viremia.

NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression.

Signaling driven by nucleic acid sensors participates in interferonopathy-mediated autoimmune diseases. NLRP12, a pyrin-containing NLR protein, is a negative regulator of innate immune activation and type I interferon (IFN-I) production. Peripheral blood mononuclear cells (PBMCs) derived from systemic lupus erythematosus (SLE) patients expressed lower levels of NLRP12, with an inverse correlation with IFNA expression and high disease activity. NLRP12 expression was transcriptionally suppressed by runt-related transcription factor 1-dependent (RUNX1-dependent) epigenetic regulation under IFN-I treatment, which enhanced a negative feedback loop between low NLRP12 expression and IFN-I production. Reduced NLRP12 protein levels in SLE monocytes was linked to spontaneous activation of innate immune signaling and hyperresponsiveness to nucleic acid stimulations. Pristane-treated Nlrp12-/- mice exhibited augmented inflammation and immune responses; and substantial lymphoid hypertrophy was characterized in NLRP12-deficient lupus-prone mice. NLRP12 deficiency mediated the increase of autoantibody production, intensive glomerular IgG deposition, monocyte recruitment, and the deterioration of kidney function. These were bound in an IFN-I signature-dependent manner in the mouse models. Collectively, we reveal a remarkable link between low NLRP12 expression and lupus progression, which suggests the impact of NLRP12 on homeostasis and immune resilience.

Adipose-Derived Stem Cell Exosomes as a Novel Anti-Inflammatory Agent and the Current Therapeutic Targets for Rheumatoid Arthritis.

Patients with rheumatoid arthritis (RA), a chronic inflammatory joint disorder, may not respond adequately to current RA treatments. Mesenchymal stem cells (MSCs) elicit several immunomodulatory and anti-inflammatory effects and, thus, have therapeutic potential. Specifically, adipose-derived stem cell (ADSC)-based RA therapy may have considerable potency in modulating the immune response, and human adipose tissue is abundant and easy to obtain. Paracrine factors, such as exosomes (Exos), contribute to ADSCs' immunomodulatory function. ADSC-Exo-based treatment can reproduce ADSCs' immunomodulatory function and overcome the limitations of traditional cell therapy. ADSC-Exos combined with current drug therapies may provide improved therapeutic effects. Using ADSC-Exos, instead of ADSCs, to treat RA may be a promising cell-free treatment strategy. This review summarizes the current knowledge of medical therapies, ADSC-based therapy, and ADSC-Exos for RA and discusses the anti-inflammatory properties of ADSCs and ADSC-Exos. Finally, this review highlights the expanding role and potential immunomodulatory activity of ADSC-Exos in patients with RA.

Increased HIF-1α expression in T cells and associated with enhanced Th17 pathway in systemic lupus erythematosus.

BACKGROUND/PURPOSE: Recent emerging evidence indicates that dysfunction of metabolic remodeling underlies aberrant T cell immune responses in systemic lupus erythematosus (SLE). This study was undertaken to investigate the expression of HIF-1α, a regulator of metabolic reprogramming, in T cells from SLE. METHODS: HIF-1α expression in T lymphocytes from SLE patients was examined by quantitative polymerase chain reaction (PCR) and the protein expression was analyzed with intracellular staining in flow cytometry. HIF-1α was overexpressed in murine CD4 T cells via transducing T cells with HIF-1α containing lentivirus. The expression of HIF-1α, metabolic- and Th17-associated genes in T cells from SLE patients and its association with clinical manifestation was analyzed. RESULTS: HIF-1α expression is increased in CD4 T cells from SLE patients both in intracellular staining and quantitative PCR analysis. In addition, there is enhanced HIF-1α expression in Th17-skewing murine T cells, and lentivirus-mediated HIF-1α overexpression promotes Th17 differentiation. Moreover, HIF-1α gene expression is positively correlated with the expression of glycolysis- and IL-17-associated genes in SLE patients. CONCLUSION: HIF-1α expression is increased in T cells from SLE patients, and is positively correlated with glycolysis- and Th17- associated pathway, implicating HIF-1α contributes to the activation of Th17 cells in SLE, and represents a potential novel therapeutic target.

T Cell-Specific Deletion of TRAIL Receptor Reveals Its Critical Role for Regulating Pathologic T Cell Activation and Disease Induction in Experimental Autoimmune Encephalomyelitis.

Recent evidence from several autoimmune animal models has demonstrated that TRAIL suppresses the activation of T cells and inhibits autoimmune inflammation via an apoptosis-independent pathway. However, it remains unclear whether the immunosuppressive effects of TRAIL are dependent on its direct effects on T cells or on other immune cells to regulate T cells for the induction of disease. Therefore, we generated mice with T cell-specific TRAIL receptor (TRAIL-R) conditional knockout to investigate the impact of TRAIL on autoimmune inflammation and disease induction in experimental autoimmune encephalomyelitis (EAE). T cell-specific TRAIL-R knockout mice were found to completely reverse the TRAIL-mediated suppression of inflammation and disease induction, indicating that TRAIL-R on T cells is essential for TRAIL-mediated suppression of inflammation and disease induction in EAE. Moreover, the immune suppression effects were not due to the induction of cell apoptosis, but to the direct inhibition of T cell activation. In addition, RNA sequencing and transcriptome analysis revealed that TRAIL-R signaling significantly downregulated the genes involved in TCR signaling pathways, T cell differentiation, and proinflammatory cytokines. These results indicate that TRAIL-R on T cells is critical for pathologic T cell activation and induction of inflammation in EAE, suggesting that TRAIL-R serves as a novel immune checkpoint receptor in T cell-mediated autoimmune diseases.

Tissue microenvironment dictates inflammation and disease activity in rheumatoid arthritis.

The recent advance in treatments for rheumatoid arthritis (RA) has significantly improved the prognosis of RA patients. However, these novel therapies do not work well for all RA patients. The unmet need suggests that the current understanding about how inflammatory response arises and progresses in RA is limited. Recent accumulating evidence reveals an important role for the tissue microenvironment in the pathogenesis of RA. The synovium, the main tissue where the RA activity occurs, is composed by a unique extracellular matrix (ECM) and residing cells. The ECM molecules provide environmental signals that determine programmed site-specific cell behavior. Improved understanding of the tissue microenvironment, especially how the synovial architecture, ECM molecules, and site-specific cell behavior promote chronic inflammation and tissue destruction, will enhance deciphering the pathogenesis of RA. Moreover, in-depth analysis of tissue microenvironment will allow us to identify potential therapeutic targets. Research is now undertaken to explore potential candidates, both cellular and ECM molecules, to develop novel therapies. This article reviews recent advances in knowledge about how changes in cellular and ECM factors within the tissue microenvironment result in propagation of chronic inflammation in RA.

High Risk of Viral Reactivation in Hepatitis B Patients with Systemic Lupus Erythematosus.

HBV reactivation (HBVr) can occur in hepatitis B surface antigen (HBsAg)-positive and negative patients. Here, we determined the incidence of HBVr and its related hepatitis in patients with systemic lupus erythematosus (SLE). From 2000 to 2017, 3307 SLE cases were retrospectively reviewed for episodes of hepatitis. The incidence, long-term outcomes and risk factors associated with HBVr, including HBsAg reverse seroconversion (RS) were analyzed. Among them, 607 had available HBsAg status. Fifty-five (9.1%) patients were positive for HBsAg and 63 (11.4%) were HBsAg-negative/antibody to hepatitis B core antigen (anti-HBc)-positive (resolved hepatitis B infection, RHB). None of them received antiviral prophylaxis before immunosuppressive treatment. During a mean 15.4 years of follow-up, 30 (54.5%) HBsAg-positive patients developed HBVr and seven (23.3%) died of liver failure, whereas only two (3.2%) RHB cases experienced HBsAg reverse seroconversion (RS). Multivariate logistic regression analysis showed that age ≥ 40 years at diagnosis of SLE (HR 5.30, p < 0.001), receiving glucocorticoid-containing immunosuppressive therapy (HR 4.78, p = 0.003), and receiving glucocorticoid ≥ 10 mg prednisolone equivalents (HR 3.68, p = 0.003) were independent risk factors for HBVr in HBsAg-positive patients. Peak level of total bilirubin ≥ 5 mg/dL during HBVr was an independent factor of mortality (p = 0.002). In conclusion, the risk of HBVr was associated with glucocorticoid daily dose. Antiviral prophylaxis is mandatory for SLE patients diagnosed at age of ≥40 years who receive ≥ 10 mg daily dose of oral prednisone or equivalent.

Chest roentgenography is complementary to interferon-gamma release assay in latent tuberculosis infection screening of rheumatic patients.

BACKGROUND: A study of latent tuberculosis infection (LTBI) burden by chest roentgenography (CXR) with reference to interferon-gamma release assay (IGRA) is still lacking in rheumatic patients of an intermediate tuberculosis burden area. METHODS: We retrospectively reviewed clinical data of patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), or psoriatic arthritis (PsA) receiving LTBI screening for biologics from Jan 2013 to April 2014. RESULTS: A total of 238 rheumatic patients who underwent LTBI screening were included in this study, of whom 46 (19.3%) had positive IGRA tests, 178 (74.8%) had negative results, and 14 (5.9%) had indeterminate results. Radiological findings suggesting healed tuberculosis (CXR-old-TB) were found in 18.1% of all patients, 23.9% in the IGRA -positive patients vs 16.9% in the IGRA-negative patients (OR 1.55 95% CI: 0.71-3.39, p = 0.27). Forty (40/46, 87.0%) IGRA-positive patients received isoniazid prophylaxis and 77.5% of them finished treatment. Six patients developed adverse effects of isoniazid treatment, resulting in an overall number needed to harm (NNH) of 6.7 (40/6). IGRA-non-positive patients with old TB-suggestive CXR comprised 13.4% (32/238) of all our rheumatic patients, and one of them developed pulmonary tuberculosis within one year after screening. CONCLUSIONS: LTBI disease burden in rheumatic patients is substantial according to the estimation of CXR and IGRA screening. Correlation between CXR and IGRA is not significant in rheumatic patients, which implies their complementary roles. IGRA-non-positive patients with old TB-suggestive CXR comprise a significant portion in rheumatic patients and merit cautious follow-up by rheumatologists, tuberculosis specialists, and pulmonologists.

Efficacy and Safety of Opinercept Tumor Necrosis Factor Inhibitor Therapy for Drug-Refractory Rheumatoid Arthritis: A Randomized Clinical Trial.

OBJECTIVES: This study aims to evaluate the efficacy and safety profile of opinercept for rheumatoid arthritis (RA) patients undergoing disease- modifying anti-rheumatic drugs (DMARDs) therapy. PATIENTS AND METHODS: A total of 98 patients with active RA (17 males, 81 females; mean age 58.6±12.2 years; range, 24.3 to 85.3 years) were randomized into opinercept plus DMARDs (OD group) or placebo plus DMARDs (PD group), in a 24-week treatment period. Primary outcome was American College of Rheumatology score (ACR20) at week 24. Other exploratory endpoints included ACR50, ACR70 and disease activity score-28 (DAS28) at week 12 and 24, tender/swollen joint counts, pain, Health Assessment Questionnaire-Disability Index, erythrocyte sedimentation rate, and C-reactive protein level. Incidence of adverse events (AEs), vital signs and physical findings, and laboratory test results were also evaluated. RESULTS: Patients in OD group showed significantly higher achievement percentage of ACR20 at week 24 than the PD group (76.6% vs. 30.3%, p<0.001). The evaluation of DAS28 was significantly improved in OD patients compared to PD patients at weeks 12 and 24. Most of the occurred AEs were mild or moderate and considered unrelated to study treatments. CONCLUSION: Opinercept concurrent with DMARDs was superior to DMARDs alone in slowing RA progression and ameliorating symptoms, with well- tolerated and acceptable safety profile.

Preserved specific anti-viral T-cell response but associated with decreased lupus activity in SLE patients with cytomegalovirus infection.

OBJECTIVES: SLE is an autoimmune disease characterized by aberrant autoantibody production and immune dysfunctions. Whether the anti-CMV immunity is impaired in SLE patients is poorly understood. We investigated the specific anti-viral T-cell response in SLE patients with CMV infection and its possible impacts on clinical manifestations in lupus. METHODS: CD28 null T-cell percentages were measured by flow cytometry in 89 SLE patients and 58 healthy controls. A specific anti-CMV CD8 T-cell response was assessed ex vivo by the production of intracellular cytokines in response to CMV phosphoprotein 65 (pp65) by flow cytometry. Clinical manifestations and immune parameters were analysed in SLE patients according to their CMV serostatus. RESULTS: CD28 null T cells were significantly expanded in SLE patients. When the anti-CMV pp65 CD8 polyfunctional T cell response was analysed, as defined by production of at least three of four functional cytokines or effectors (intracellular IFN-γ, IL-2, TNF-α and surface CD107a), the results demonstrated that it was not impaired in SLE patients. In contrast, when comparing clinical manifestations, there were lower anti-ds-DNA levels and decreased SLEDAI in SLE patients with CMV infection. Furthermore, the expansion of CD4+CD28 null T cells was negatively associated with anti-ds-DNA levels and SLEDAI in these lupus patients. CONCLUSION: In SLE patients with CMV infection, the specific anti-CMV CD8 T-cell response is preserved but is associated with decreased disease activity and lower anti-DNA levels among these patients, suggesting CMV infection may mitigate lupus activity.

Factors associated with depressive symptoms in patients with ankylosing spondylitis in Northern Taiwan.

Patients with ankylosing spondylitis (AS) experience impaired physical function and reduced quality of life, which puts this group at high risk for depression. Identifying factors associated with depressive symptoms could improve outcomes for this at-risk group. However, few studies have examined the relationship between demographic and clinical variables and depressive symptoms in patients with AS. This cross-sectional correlation study recruited patients with AS by convenience sampling from the division of immunology and rheumatology of a medical center in Northern Taiwan. Participants (N = 120) included 91 males and 29 females, age ≥ 20 years. Data were collected from chart reviews, and structural questionnaires, which included demographic information regarding employment status, history of falls, impact of AS on work; clinical information relative to AS was obtained from structural questionnaires: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and functional index (BASFI), Numerical Rating Scale (NRS), Body Image Scale (BIS), and Beck Depression Inventory-II (BDI-II). Multiple regression analysis identified predictors of depression. The mean BDI-II score was 9.50 ± 8.30; 25% had scores indicating mild to severe depressive symptoms. Mean score on the BIS was 68.17 ± 16.14; 14.2% had fallen within the previous year; and 57.5% reported AS affected their work. Variables associated with depressive symptoms were work affected by AS (ß = 0.14, p = .049), occurrence of a fall within the previous year (ß = 0.14, p = .032), higher scores on the BASDAI (ß = 0.21, p = .032), and lower body image (ß = -0.38, p < .001). Clinical professionals should regularly assess patients with AS for depressive symptoms. Health care planning should provide instruction in fall prevention and control of disease activity, and strategies to improve body image, which could improve patients' self-management capabilities and body image as well as mitigate depressive symptoms.

TRAIL inhibits RANK signaling and suppresses osteoclast activation via inhibiting lipid raft assembly and TRAF6 recruitment.

Human osteoclast formation from mononuclear phagocyte precursors involves interactions between members of the tumor necrosis factor (TNF) ligand superfamily and their receptors. Recent evidence indicated that TNF-α-related apoptosis-inducing ligand (TRAIL) induces osteoclast differentiation via a TRAF6-dependent signaling pathway; but paradoxically, it inhibits RANK ligand (RANKL)-induced osteoclast differentiation. Although a number of signaling pathways were linked to the RANK and osteoclastogenesis, it is not known how TRAIL regulates RANK signaling. In this study, we demonstrate that TRAIL regulates RANK-induced osteoclastogenesis in terms of the assembly of lipid raft-associated signaling complexes. RANKL stimulation induced recruitment of TRAF6, c-Src, and DAP-12 into lipid rafts. However, the RANKL-induced assembly of lipid raft-associated signaling complexes and TRAF6 recruitment was abolished in the presence of TRAIL. TRAIL-induced dissociation of RANKL-induced lipid raft signaling complexes was reversed by treatment with TRAIL receptor (TRAIL-R) siRNA or an anti-TRAIL-R blocking antibody, indicating that TRAIL mediates suppression of RANKL-induced lipid raft signaling via interactions with TRAIL-R. Finally, we demonstrated that TRAIL suppressed inflammation-induced bone resorption and osteoclastogenesis in a collagen-induced arthritis (CIA) rat animal model. Our results provide a novel apoptosis-independent role of TRAIL in regulating RANK signaling and suppresses osteoclast activation via inhibiting lipid raft assembly and TRAF6 recruitment.

Anti-cytomegalovirus IgG antibody titer is positively associated with advanced T cell differentiation and coronary artery disease in end-stage renal disease.

BACKGROUND: Accumulating evidence indicates that persistent human cytomegalovirus (HCMV) infection is associated with several health-related adverse outcomes including atherosclerosis and premature mortality in individuals with normal renal function. Patients with end-stage renal disease (ESRD) exhibit impaired immune function and thus may face higher risk of HCMV-related adverse outcomes. Whether the level of anti-HCMV immune response may be associated with the prognosis of hemodialysis patients is unknown. RESULTS: Among 412 of the immunity in ESRD study (iESRD study) participants, 408 were HCMV seropositive and were analyzed. Compared to 57 healthy individuals, ESRD patients had higher levels of anti-HCMV IgG. In a multivariate-adjusted logistic regression model, the log level of anti-HCMV IgG was independently associated with prevalent coronary artery disease (OR = 1.93, 95% CI = 1.2~ 3.2, p = 0.01) after adjusting for age, sex, hemoglobin, diabetes, calcium phosphate product and high sensitivity C-reactive protein. Levels of anti-HCMV IgG also positively correlated with both the percentage and absolute number of terminally differentiated CD8+ and CD4+ CD45RA+ CCR7- TEMRA cells, indicating that immunosenescence may participate in the development of coronary artery disease. CONCLUSION: This is the first study showing that the magnitude of anti-HCMV humoral immune response positively correlates with T cell immunosenescence and coronary artery disease in ESRD patients. The impact of persistent HCMV infection should be further investigated in this special patient population.

TRAIL-Mediated Suppression of T Cell Receptor Signaling Inhibits T Cell Activation and Inflammation in Experimental Autoimmune Encephalomyelitis.

Objective: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell apoptosis by transducing apoptosis signals after interacting with its receptor (TRAIL-R). Although the actual biological role of TRAIL remains to be elucidated, recent accumulating evidence implies that TRAIL regulates immune responses and immune cell homeostasis via an apoptosis-independent pathway, suggesting a novel immune-regulatory role of TRAIL in autoimmune diseases. The purpose of this study is to address the immune-regulatory role and molecular mechanism of TRAIL in regulating T cell activation in autoimmune diseases. Design: TRAIL was administered to mice to induce experimental autoimmune encephalomyelitis (EAE), and to evaluate its impact on neuroinflammation and disease activity. The effects of TRAIL on neuroantigen [myelin oligodendrocyte glycoprotein (MOG)35-55]-activated T cell proliferation and cytokine production were investigated. TRAIL-treated MOG35-55-activated splenic Th17 cells were further adoptively transferred into Rag1 KO mice to induce passive EAE. Gene expression profiles of CD4+ T cells from EAE mice treated with TRAIL were analyzed by RNA sequencing and transcriptome analysis. Results: TRAIL suppressed autoimmune encephalomyelitis and inhibited T cell reactivity to neuro-antigen in murine EAE, and the effects were dependent on TRAIL-R signaling. Moreover, TRAIL directly inhibited activation of MOG35-55-activated CD4+ T cells, resulting in suppression of neuroinflammation and reduced disease activity in adoptive transfer-induced EAE. Furthermore, TRAIL-R signaling inhibited phosphorylation of proximal T cell receptor (TCR)-associated tyrosine kinases in activated CD4+ T cells. Importantly, TRAIL/TRAIL-R interaction downregulated TCR downstream signaling genes in RNA sequencing and transcriptome analysis. Conclusion: TRAIL/TRAIL-R interaction regulates CD4+ T cell activation in autoimmune inflammation and directly suppresses T cell activation via inhibiting TCR signaling, suggesting that TRAIL-R serves as a novel immune checkpoint in T cell responses.

An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis.

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.

Correction: Chronic Hepatitis C Virus Infection Is Associated with the Development of Rheumatoid Arthritis: A Nationwide Population-Based Study in Taiwan.

[This corrects the article DOI: 10.1371/journal.pone.0113579.].

Correction: Association of Sjögren's Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0161958.].