TREML4 receptor regulates inflammation and innate immune cell death during polymicrobial sepsis.

Sepsis is a biphasic disease characterized by an acute inflammatory response, followed by a prolonged immunosuppressive phase. Therapies aimed at controlling inflammation help to reduce the time patients with sepsis spend in intensive care units, but they do not lead to a reduction in overall mortality. Recently, the focus has been on addressing the immunosuppressive phase, often caused by apoptosis of immune cells. However, molecular triggers of these events are not yet known. Using whole-genome CRISPR screening in mice, we identified a triggering receptor expressed on myeloid cells (TREM) family receptor, TREML4, as a key regulator of inflammation and immune cell death in sepsis. Genetic ablation of Treml4 in mice demonstrated that TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the endoplasmic reticulum stress response and apoptotic cell death in innate immune cells, leading to an overall increase in survival rate, both during the acute and chronic phases of polymicrobial sepsis.

CD8+ T cells specific for an immunodominant SARS-CoV-2 nucleocapsid epitope cross-react with selective seasonal coronaviruses.

Efforts are being made worldwide to understand the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, including the impact of T cell immunity and cross-recognition with seasonal coronaviruses. Screening of SARS-CoV-2 peptide pools revealed that the nucleocapsid (N) protein induced an immunodominant response in HLA-B7+ COVID-19-recovered individuals that was also detectable in unexposed donors. A single N-encoded epitope that was highly conserved across circulating coronaviruses drove this immunodominant response. In vitro peptide stimulation and crystal structure analyses revealed T cell-mediated cross-reactivity toward circulating OC43 and HKU-1 betacoronaviruses but not 229E or NL63 alphacoronaviruses because of different peptide conformations. T cell receptor (TCR) sequencing indicated that cross-reactivity was driven by private TCR repertoires with a bias for TRBV27 and a long CDR3ß loop. Our findings demonstrate the basis of selective T cell cross-reactivity for an immunodominant SARS-CoV-2 epitope and its homologs from seasonal coronaviruses, suggesting long-lasting protective immunity.

Extracellular vesicles as next generation immunotherapeutics.

Extracellular vesicles (EVs) function as a mode of intercellular communication and molecular transfer to elicit diverse biological/functional response. Accumulating evidence has highlighted that EVs from immune, tumour, stromal cells and even bacteria and parasites mediate the communication of various immune cell types to dynamically regulate host immune response. EVs have an innate capacity to evade recognition, transport and transfer functional components to target cells, with subsequent removal by the immune system, where the immunological activities of EVs impact immunoregulation including modulation of antigen presentation and cross-dressing, immune activation, immune suppression, and immune surveillance, impacting the tumour immune microenvironment. In this review, we outline the recent progress of EVs in immunorecognition and therapeutic intervention in cancer, including vaccine and targeted drug delivery and summarise their utility towards clinical translation. We highlight the strategies where EVs (natural and engineered) are being employed as a therapeutic approach for immunogenicity, tumoricidal function, and vaccine development, termed immuno-EVs. With seminal studies providing significant progress in the sequential development of engineered EVs as therapeutic anti-tumour platforms, we now require direct assessment to tune and improve the efficacy of resulting immune responses - essential in their translation into the clinic. We believe such a review could strengthen our understanding of the progress in EV immunobiology and facilitate advances in engineering EVs for the development of novel EV-based immunotherapeutics as a platform for cancer treatment.

HLA-A*11:01-restricted CD8+ T cell immunity against influenza A and influenza B viruses in Indigenous and non-Indigenous people.

HLA-A*11:01 is one of the most prevalent human leukocyte antigens (HLAs), especially in East Asian and Oceanian populations. It is also highly expressed in Indigenous people who are at high risk of severe influenza disease. As CD8+ T cells can provide broadly cross-reactive immunity to distinct influenza strains and subtypes, including influenza A, B and C viruses, understanding CD8+ T cell immunity to influenza viruses across prominent HLA types is needed to rationally design a universal influenza vaccine and generate protective immunity especially for high-risk populations. As only a handful of HLA-A*11:01-restricted CD8+ T cell epitopes have been described for influenza A viruses (IAVs) and epitopes for influenza B viruses (IBVs) were still unknown, we embarked on an epitope discovery study to define a CD8+ T cell landscape for HLA-A*11:01-expressing Indigenous and non-Indigenous Australian people. Using mass-spectrometry, we identified IAV- and IBV-derived peptides presented by HLA-A*11:01 during infection. 79 IAV and 57 IBV peptides were subsequently screened for immunogenicity in vitro with peripheral blood mononuclear cells from HLA-A*11:01-expressing Indigenous and non-Indigenous Australian donors. CD8+ T cell immunogenicity screening revealed two immunogenic IAV epitopes (A11/PB2320-331 and A11/PB2323-331) and the first HLA-A*11:01-restricted IBV epitopes (A11/M41-49, A11/NS1186-195 and A11/NP511-520). The immunogenic IAV- and IBV-derived peptides were >90% conserved among their respective influenza viruses. Identification of novel immunogenic HLA-A*11:01-restricted CD8+ T cell epitopes has implications for understanding how CD8+ T cell immunity is generated towards IAVs and IBVs. These findings can inform the development of rationally designed, broadly cross-reactive influenza vaccines to ensure protection from severe influenza disease in HLA-A*11:01-expressing individuals.

NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8⁺ T cells.

Memory T cells exert antigen-independent effector functions, but how these responses are regulated is unclear. We discovered an in vivo link between flagellin-induced NLRC4 inflammasome activation in splenic dendritic cells (DCs) and host protective interferon-γ (IFN-γ) secretion by noncognate memory CD8(+) T cells, which could be activated by Salmonella enterica serovar Typhimurium, Yersinia pseudotuberculosis and Pseudomonas aeruginosa. We show that CD8α(+) DCs were particularly efficient at sensing bacterial flagellin through NLRC4 inflammasomes. Although this activation released interleukin 18 (IL-18) and IL-1ß, only IL-18 was required for IFN-γ production by memory CD8(+) T cells. Conversely, only the release of IL-1ß, but not IL-18, depended on priming signals mediated by Toll-like receptors. These findings provide a comprehensive mechanistic framework for the regulation of noncognate memory T cell responses during bacterial immunity.

CD39hi identifies an exhausted tumor-reactive CD8+ T cell population associated with tumor progression in human gastric cancer.

The ectonucleotidase CD39 has been regarded as a promising immune checkpoint in solid tumors. However, the expression of CD39 by tumor-infiltrating CD8+ T cells as well as their potential roles and clinical implications in human gastric cancer (GC) remain largely unknown. Here, we found that GC-infiltrating CD8+ T cells contained a fraction of CD39hi cells that constituted about 6.6% of total CD8+ T cells in tumors. These CD39hi cells enriched for GC-infiltrating CD8+ T cells with features of exhaustion in transcriptional, phenotypic, metabolic and functional profiles. Additionally, GC-infiltrating CD39hiCD8+ T cells were also identified for tumor-reactive T cells, as these cells expanded in vitro were able to recognize autologous tumor organoids and induced more tumor cell apoptosis than those of expanded their CD39int and CD39-CD8+ counterparts. Furthermore, CD39 enzymatic activity controlled GC-infiltrating CD39hiCD8+ T cell effector function, and blockade of CD39 efficiently enhanced their production of cytokines IFN-γ and TNF-α. Finally, high percentages of GC-infiltrating CD39hiCD8+ T cells correlated with tumor progression and independently predicted patients' poor overall survival. These findings provide novel insights into the association of CD39 expression level on CD8+ T cells with their features and potential clinical implications in GC, and empowering those exhausted tumor-reactive CD39hiCD8+ T cells through CD39 inhibition to circumvent the suppressor program may be an attractive therapeutic strategy against GC.

Fangchinoline Inhibits African Swine Fever Virus Replication by Suppressing the AKT/mTOR/NF-κB Signaling Pathway in Porcine Alveolar Macrophages.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is one of the most important infectious diseases that cause high morbidity and mortality in pigs and substantial economic losses to the pork industry of affected countries due to the lack of effective vaccines. The need to develop alternative robust antiviral countermeasures, especially anti-ASFV agents, is of the utmost urgency. This study shows that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid found in the roots of Stephania tetrandra of the family Menispermaceae, significantly inhibits ASFV replication in porcine alveolar macrophages (PAMs) at micromolar concentrations (IC50 = 1.66 µM). Mechanistically, the infection of ASFV triggers the AKT/mTOR/NF-κB signaling pathway. FAN significantly inhibits ASFV-induced activation of such pathways, thereby suppressing viral replication. Such a mechanism was confirmed using an AKT inhibitor MK2206 as it inhibited AKT phosphorylation and ASFV replication in PAMs. Altogether, the results suggest that the AKT/mTOR pathway could potentially serve as a treatment strategy for combating ASFV infection and that FAN could potentially emerge as an effective novel antiviral agent against ASFV infections and deserves further in vivo antiviral evaluations.

The Antimalaria Drug Artesunate Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by Activating AMPK and Nrf2/HO-1 Signaling Pathways.

Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide. Currently, vaccine strategies provide limited protection against PRRSV transmission, and no effective drug is commercially available. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV pandemics. This study showed that artesunate (AS), one of the antimalarial drugs, potently suppressed PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs) at micromolar concentrations. Furthermore, we demonstrated that this suppression was closely associated with AS-activated AMPK (energy homeostasis) and Nrf2/HO-1 (inflammation) signaling pathways. AS treatment promoted p-AMPK, Nrf2, and HO-1 expression and, thus, inhibited PRRSV replication in Marc-145 and PAM cells in a time- and dose-dependent manner. These effects of AS were reversed when the AMPK or HO-1 gene was silenced by short interfering RNA. In addition, we demonstrated that AMPK works upstream of Nrf2/HO-1, as its activation by AS is AMPK dependent. Adenosine phosphate analysis showed that AS activates AMPK via improving the AMP/ADP-to-ATP ratio rather than direct interaction with AMPK. Altogether, our findings indicate that AS is a promising novel therapeutic for controlling PRRSV and that its anti-PRRSV mechanism, which involves the functional link between energy homeostasis and inflammation suppression pathways, may provide opportunities for developing novel antiviral agents. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) infections have continuously threatened the pork industry worldwide. Vaccination strategies provide very limited protection against PRRSV infection, and no effective drug is commercially available. We show that artesunate (AS), one of the antimalarial drugs, is a potent inhibitor against PRRSV replication in Marc-145 cells and ex vivo primary porcine alveolar macrophages (PAMs). Furthermore, we demonstrate that AS inhibits PRRSV replication via activation of AMPK-dependent Nrf2/HO-1 signaling pathways, revealing a novel link between energy homeostasis (AMPK) and inflammation suppression (Nrf2/HO-1) during viral infection. Therefore, we believe that AS may be a promising novel therapeutics for controlling PRRSV, and its anti-PRRSV mechanism may provide a strategy to develop novel antiviral agents.

Suboptimal SARS-CoV-2-specific CD8+ T cell response associated with the prominent HLA-A*02:01 phenotype.

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2-specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLA-A*02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/S269-277 and A2/Orf1ab3183-3191 Using peptide-HLA tetramer enrichment, direct ex vivo assessment of A2/S269+CD8+ and A2/Orf1ab3183+CD8+ populations indicated that A2/S269+CD8+ T cells were detected at comparable frequencies (∼1.3 × 10-5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10-6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein-Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10-4) populations. Phenotyping A2/S269+CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269+CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269+CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19.

Antiviral Effect of Ginsenosides rk1 against Influenza a Virus Infection by Targeting the Hemagglutinin 1-Mediated Virus Attachment.

Influenza A virus (IAV) infections have been a serious hazard to public health everywhere. With the growing concern of drug-resistant IAV strains, there is an urgent need for novel anti-IAV medications, especially those with alternative mechanisms of action. Hemagglutinin (HA), an IAV glycoprotein, plays critical roles in the early stage of virus infection, including receptor binding and membrane fusion, making it a good target for developing anti-IAV drugs. Panax ginseng is a widely used herb in traditional medicine with extensive biological effects in various disease models, and its extract was reported to show protection in IAV-infected mice. However, the main effective anti-IAV constituents in panax ginseng remain unclear. Here, we report that ginsenoside rk1 (G-rk1) and G-rg5, out of the 23 screened ginsenosides, exhibit significant antiviral effects against 3 different IAV subtypes (H1N1, H5N1, and H3N2) in vitro. Mechanistically, G-rk1 blocked IAV binding to sialic acid in a hemagglutination inhibition (HAI) assay and an indirect ELISA assay; more importantly, we showed that G-rk1 interacted with HA1 in a dose-dependent manner in a surface plasmon resonance (SPR) analysis. Furthermore, G-rk1 treatment by intranasal inoculation effectively reduced the weight loss and mortality of mice challenged with a lethal dose of influenza virus A/Puerto Rico/8/34 (PR8). In conclusion, our findings reveal for the first time that G-rk1 possesses potent anti-IAV effects in vitro and in vivo. We have also identified and characterized with a direct binding assay a novel ginseng-derived IAV HA1 inhibitor for the first time, which could present potential approaches to prevent and treat IAV infections.

Distribution, phenotype, functional and clinical relevance of CD8+CD103+ tissue-resident memory T cells in human gastric cancer.

CD8+CD103+ tissue-resident memory T cells (TRMs) are involved in tumor immune response and linked to favorable clinical outcome in human cancer. However, the distribution, phenotype, functional properties and clinical relevance of these cells in gastric cancer (GC) remain elusive. Here, our data show that, in comparison to non-tumor tissues, the percentages of CD8+CD103+ TRMs in tumors are significantly decreased. Most tumor-infiltrating CD8+CD103+ TRMs are CD45RA-CCR7- effector-memory cells with higher PD-1 and 4-1BB expression than those from non-tumor tissues. Further, tumor-infiltrating CD8+CD103+ TRMs show impaired cytolytic capacity due to decreased granzyme B and perforin expression. Moreover, ex vivo PD-1 blockade could restore the cytolytic capacity of tumor-infiltrating CD8+CD103+ TRMs, and such anti-PD-1-mediated reinvigoration of CD8+CD103+ TRMs could be further enhanced by 4-1BB co-stimulation. Finally, lower levels of Tumor-infiltrating CD8+CD103+ TRMs are positively correlated with GC progression and poor patients' survival. Our data suggest that restoring CD8+CD103+ TRM function by combining PD-1 blockade and 4-1BB co-stimulation may be a promising strategy for treating GC.

Toosendanin activates caspase-1 and induces maturation of IL-1ß to inhibit type 2 porcine reproductive and respiratory syndrome virus replication via an IFI16-dependent pathway.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a prevalent and endemic swine pathogen which causes significant economic losses in the global swine industry. Multiple vaccines have been developed to prevent PRRSV infection. However, they provide limited protection. Moreover, no effective therapeutic drugs are yet available. Therefore, there is an urgent need to develop novel antiviral strategies to prevent PRRSV infection and transmission. Here we report that Toosendanin (TSN), a tetracyclic triterpene found in the bark or fruits of Melia toosendan Sieb. et Zucc., strongly suppressed type 2 PRRSV replication in vitro in Marc-145 cells and ex vivo in primary porcine alveolar macrophages (PAMs) at sub-micromolar concentrations. The results of transcriptomics revealed that TSN up-regulated the expression of IFI16 in Marc-145 cells. Furthermore, we found that IFI16 silencing enhanced the replication of PRRSV in Marc-145 cells and that the anti-PRRSV activity of TSN was dampened by IFI16 silencing, suggesting that the inhibition of TSN against PRRSV replication is IFI16-dependent. In addition, we showed that TSN activated caspase-1 and induced maturation of IL-1ß in an IFI16-dependent pathway. To verify the role of IL-1ß in PRRSV infection, we analyzed the effect of exogenous rmIL-1ß on PRRSV replication, and the results showed that exogenous IL-1ß significantly inhibited PRRSV replication in Marc-145 cells and PAMs in a dose-dependent manner. Altogether, our findings indicate that TSN significantly inhibits PRRSV replication at very low concentrations (EC50: 0.16-0.20 µM) and may provide opportunities for developing novel anti-PRRSV agents.

Influenza virus infection selectively triggers the accumulation and persistence of more potent Helios-expressing Foxp3+ regulatory T cells in the lungs.

Foxp3+ regulatory T cells (Tregs) represent a special lineage of CD4+ T cells. Analysis of Treg response during primary and secondary influenza virus infection clearly demonstrates a robust accumulation of Tregs into the infected lungs and the existence of a population of long-lived antigen-specific memory Tregs in the same tissues after resolution of the infection. However, it remains unknown whether these Tregs co-express Helios, a member of the Ikaros transcription factor family. In this study, Foxp3+ Helios+ and Foxp3+ Helios- Tregs in the lungs, mLNs and spleens of influenza virus-infected and uninfected control mice were tracked. The data show that while there is a co-existence of Foxp3+ Helios+ and Foxp3+ Helios- Tregs in the tissues, the accumulated Tregs in the lungs and lung-draining mediastinal lymph nodes (mLNs) of the infected mice are highly enriched for Foxp3+ Helios+ cells. It was further demonstrated that, after the clearance of primary infection, Foxp3+ Helios+ cells have the ability to persist in the tissues over their Helios- counterparts. More importantly, Foxp3+ Helios+ Tregs accumulated in an accelerated kinetics during recall response to reinfection. In vitro analysis of Treg suppressive function revealed that Foxp3+ Helios+ Tregs are more capable of suppressing influenza virus-specific CD8+ T cell activation, cytokine production and proliferation. Together, the data provide new insights into Treg responses during primary and secondary influenza virus infection and suggest that Foxp3+ Helios+ Tregs predominantly drive the Treg responses.

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p-STAT3 in Helicobacter pylori-associated gastritis.

BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.

Semiquantitative Proteomics Enables Mapping of Murine Neutrophil Dynamics following Lethal Influenza Virus Infection.

Neutrophils are rapidly deployed innate immune cells, and excessive recruitment is causally associated with influenza-induced pathologic conditions. Despite this, the complete set of influenza lethality-associated neutrophil effector proteins is currently unknown. Whether the expression of these proteins is predetermined during bone marrow (BM) neutrophil maturation or further modulated by tissue compartment transitions has also not been comprehensively characterized at a proteome-wide scale. In this study, we used high-resolution mass spectrometry to map how the proteomes of murine neutrophils change comparatively across BM, blood, and the alveolar airspaces to deploy an influenza lethality-associated response. Following lethal influenza infection, mature neutrophils undergo two infection-dependent and one context-independent compartmental transitions. Translation of type I IFN-stimulated genes is first elevated in the BM, preceding the context-independent downregulation of ribosomal proteins observed in blood neutrophils. Following alveolar airspace infiltration, the bronchoalveolar lavage (BAL) neutrophil proteome is further characterized by a limited increase in type I IFN-stimulated and metal-sequestering proteins as well as a decrease in degranulation-associated proteins. An influenza-selective and dose-dependent increase in antiviral and lipid metabolism-associated proteins was also observed in BAL neutrophils, indicative of a modest capacity for pathogen response tuning. Altogether, our study provides new and comprehensive evidence that the BAL neutrophil proteome is shaped by BM neutrophil maturation as well as subsequent compartmental transitions following lethal influenza infection.

Influenza A Virus Infection Induces Viral and Cellular Defective Ribosomal Products Encoded by Alternative Reading Frames.

The importance of antiviral CD8+ T cell recognition of alternative reading frame (ARF)-derived peptides is uncertain. In this study, we describe an epitope (NS1-ARF21-8) present in a predicted 14-residue peptide encoded by the +1 register of NS1 mRNA in the influenza A virus (IAV). NS1-ARF21-8 elicits a robust, highly functional CD8+ T cell response in IAV-infected BALB/c mice. NS1-ARF21-8 is presented from unspliced NS mRNA, likely from downstream initiation on a Met residue that comprises the P1 position of NS1-ARF21-8 Derived from a 14-residue peptide with no apparent biological function and negligible impacts on IAV infection, infectivity, and pathogenicity, NS1-ARF21-8 provides a clear demonstration of how immunosurveillance exploits natural errors in protein translation to provide antiviral immunity. We further show that IAV infection enhances a model cellular ARF translation, which potentially has important implications for virus-induced autoimmunity.

Upregulation of Tubulointerstitial nephritis antigen like 1 promotes gastric cancer growth and metastasis by regulating multiple matrix metallopeptidase expression.

BACKGROUND AND AIM: Tubulointerstitial nephritis antigen-like 1 (TINAGL1), as a novel matricellular protein, has been demonstrated to participate in cancer progression, whereas the potential function of TINAGL1 in gastric cancer (GC) remains unknown. METHODS: The expression pattern of TINAGL1 in GC was examined by immunohistochemistry, ELISA, real-time polymerase chain reaction, and Western blot. Correlation between TINAGL1 and matrix metalloproteinases (MMPs) was analyzed by the GEPIA website and Kaplan-Meier plots database. The lentivirus-based TINAGL1 knockdown, CCK-8, and transwell assays were used to test the function of TINAGL1 in vitro. The role of TINAGL1 was confirmed by subcutaneous xenograft, abdominal dissemination, and lung metastasis model. Microarray experiments, ELISA, real-time polymerase chain reaction, and Western blot were used to identify molecular mechanism. RESULTS: TINAGL1 was increased in GC tumor tissues and associated with poor patient survival. Moreover, TINAGL1 significantly promoted GC cell proliferation and migration in vitro as well as facilitated GC tumor growth and metastasis in vivo. TINAGL1 expression in GC cells was accompanied with increasing MMPs including MMP2, MMP9, MMP11, MMP14, and MMP16. GEPIA database revealed that these MMPs were correlated with TINAGL1 in GC tumors and that the most highly expressed MMP was MMP2. Mechanically, TINAGL1 regulated MMP2 through the JNK signaling pathway activation. CONCLUSIONS: Our data highlight that TINAGL1 promotes GC growth and metastasis and regulates MMP2 expression, indicating that TINAGL1 may serve as a therapeutic target for GC.

Host CD8α+ and CD103+ dendritic cells prime transplant antigen-specific CD8+ T cells via cross-dressing.

The participation of dendritic cells (DCs) in CD8+ T-cell-mediated allograft rejection is a long-standing question of great clinical relevance for tissue transplantation. Here, we show that Batf3-/- mice demonstrate delayed allo-skin graft rejection and are deficient in priming allo-specific CD8+ T cells. Batf3-/- mouse priming is restored by transferring either purified CD8α+ or CD103+ DCs, demonstrating the critical role of these cells in alloreactivity. Using Db -restricted antiviral F5 transgenic T-cell receptor T cells, which we demonstrate are alloreactive with H-2Kd , we show that cross-dressing of CD8α+ and CD103+ primes CD8+ T-cell or allo-specific responses in vitro and in vivo. These findings suggest novel strategies for moderating tissue rejection based on interfering with DC cross-dressing or subsequent interaction with T cells.

Abrogation of cathepsin C by Helicobacter pylori impairs neutrophil activation to promote gastric infection.

Cathepsin C (CtsC) functions as a central coordinator for activation of many serine proteases in immune cells. However, CtsC expression in gastric epithelial cells and its role in Helicobacter pylori infection remain unclear. Real-time PCR, Western blot, and immunohistochemistry analyses identified that CtsC was decreased in gastric mucosa of H. pylori-infected patients and mice. Isolated gastric epithelial cells and cell lines were stimulated with H. pylori and/or TGF-ß1 showed that down-regulation of CtsC in gastric epithelial cells largely depended on H. pylori cagA via Src/ERK and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways, and the effect could be synergistically augmented by TGF-ß1 in an autocrine manner. In human gastric mucosa, CtsC expression was negatively correlated with bacteria colonization; accordingly, provision of exogenous active CtsC overwhelmed H. pylori persistence in gastric mucosa of mice. In the presence of active CtsC, isolated human neutrophils activated via NF-κB pathway with augmented bactericidal capacity in vitro. We also found that neutrophils activated and cleared bacteria in active CtsC-injected mice and that there was no bactericidal capacity in mice that were simultaneously neutrophil-depleted by Ly6G antibody. Our findings identified a mechanism that H. pylori abrogate CtsC to impair neutrophil activation and to ensure persistence in gastric mucosa. Efforts to enable and boost this neutrophil activation pathway by active CtsC may therefore become valuable strategies in treating H. pylori infection.-Liu, Y. G., Teng, Y. S., Cheng, P., Kong, H., Lv, Y. P., Mao, F. Y., Wu, X. L., Hao, C. J., Chen, W., Yang, S. M., Zhang, J. Y., Peng, L. S., Wang, T. T., Han, B., Ma, Q., Zou, Q. M., Zhuang, Y. Abrogation of cathepsin C by Helicobacter pylori impairs neutrophil activation to promote gastric infection.

Progress on chicken T cell immunity to viruses.

Avian virus infection remains one of the most important threats to the poultry industry. Pathogens such as avian influenza virus (AIV), avian infectious bronchitis virus (IBV), and infectious bursal disease virus (IBDV) are normally controlled by antibodies specific for surface proteins and cellular immune responses. However, standard vaccines aimed at inducing neutralizing antibodies must be administered annually and can be rendered ineffective because immune-selective pressure results in the continuous mutation of viral surface proteins of different strains circulating from year to year. Chicken T cells have been shown to play a crucial role in fighting virus infection, offering lasting and cross-strain protection, and offer the potential for developing universal vaccines. This review provides an overview of our current knowledge of chicken T cell immunity to viruses. More importantly, we point out the limitations and barriers of current research and a potential direction for future studies.