Reduction Of Treg Cells Research Articles

Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid-Derived Suppressor Cells.

Myeloid-derived suppressor cells (MDSC) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T-cell-mediated antitumor immunity, but mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduce MDSC activity. Using in vitro T-cell proliferation assays, data show that HDL NPs specifically bind SCARB1 to inhibit MDSC activity. In murine cancer models, HDL NP treatment significantly reduces tumor growth, metastatic tumor burden, and increases survival due to enhanced adaptive immunity. Flow cytometry and IHC demonstrate that HDL NP-mediated suppression of MDSCs increased CD8+ T cells and reduced Treg cells in the metastatic tumor microenvironment. Using transgenic mice lacking SCARB1, in vivo data clearly show that the HDL NPs specifically target this receptor for suppressing MDSCs. Ultimately, our data provide a new mechanism and targeted therapy, HDL NPs, to modulate a critical innate immune cell checkpoint to enhance the immune response to cancer. Mol Cancer Ther; 17(3); 686-97. ©2017 AACR.

Taking aim at regulatory T cells

Cancer Immunotherapy Cancer immunotherapy attempts to stimulate the patient's immune system against a tumor, but it can be limited by the suppressive effects of the patient's own regulatory T (Treg) cells. Nie et al. showed that coinhibiting a TNF (tumor necrosis factor) receptor reduced Treg cell activity and proliferation, stimulated antitumor immune memory, and even shrank colon and breast tumors in mice that were unresponsive to common single-agent immunotherapies. Thus, adding anti-TNF therapeutics may help to increase and broaden the efficacy of immunotherapy for cancer patients. Sci. Signal. 10 , eaan0790 (2018).

Early and Partial Reduction in CD4+Foxp3+ Regulatory T Cells during Colitis-Associated Colon Cancer Induces CD4+ and CD8+ T Cell Activation Inhibiting Tumorigenesis

Colorectal cancer (CRC) is the second most commonly diagnosed cancer in women and the third in men in North America and Europe. CRC is associated with inflammatory responses in which intestinal pathology is caused by different cell populations including a T cell dysregulation that concludes in an imbalance between activated T (Tact) and regulatory T (Treg) cells. Treg cells are CD4+Foxp3+ cells that actively suppress pathological and physiological immune responses, contributing to the maintenance of immune homeostasis. A tumor-promoting function for Treg cells has been suggested in CRC, but the kinetics of Treg cells during CRC development are poorly known. Therefore, using a mouse model of colitis-associated colon cancer (CAC) induced by azoxymethane and dextran sodium sulfate, we observed the dynamic and differential kinetics of Treg cells in blood, spleen and mesenteric lymph nodes (MLNs) as CAC progresses, highlighting a significant reduction in Treg cells in blood and spleen during early CAC development, whereas increasing percentages of Treg cells were detected in late stages in MLNs. Interestingly, when Treg cells were decreased, Tact cells were increased and vice versa. Treg cells from late stages of CAC displayed an activated phenotype by expressing PD1, CD127 and Tim-3, suggesting an increased suppressive capacity. Suppression assays showed that T-CD4+ and T-CD8+ cells were suppressed more efficiently by MLN Treg cells from CAC animals. Finally, an antibody-mediated reduction in Treg cells during early CAC development resulted in a better prognostic value, because animals showed a reduction in tumor progression associated with an increased percentage of activated CD4+CD25+Foxp3- and CD8+CD25+ T cells in MLNs, suggesting that Treg cells suppress T cell activation at early steps during CAC development.

The Plasticity of CD4+CD25+FOXP3+CD127low T Cells in Patients with Metastatic Renal Cell Carcinoma in the Course of Interferon-Alpha Immunotherapy.

Aims To examine changes in subpopulation of CD4+CD25+Foxp3+CD127low T lymphocytes (Treg) and their association with the efficiency of the IFN-α therapy. Materials and Methods Pts with mRCC who had undergone nephrectomy were treated with IFN-α at a dose of 6 × 106 U/day three times a week (n = 18). An immunophenotypic analysis of lymphocytes in peripheral blood expressing CD4, CD25, CD127, and Foxp3 antigens could be performed in 18 pts before, 2 weeks, and 2 mo after IFN-α therapy and 22 normal volunteers. Blood samples were collected at baseline and 2 mo after treatment start. Serum levels of TGF-β1, IL-17A, and Epo were measured by ELISA. Results PR was achieved in 3 (16.6%) pts who received first-line therapy. Long-lasting SD (≥6 months) was noted in 6 (33.3%) pts. The median progression free survival (PFS) was 4 mo (95% CI: 2-NE). The study of the population of Treg indicated that there were no significant differences in the groups depending on the effect (p = 0.71). In one patient, the reduction of Treg cells was associated with increased TGF-β and IL-17 levels, whereas in other two pts the increase in Treg cells was associated with decreased TGF-β and IL-17 levels. The endogenous levels of Epo did not show significant correlation with response to IFN-α immunotherapy. In the patient subgroup with an initial value of MCH > 31 pg, the median PFS was not achieved, but in the subgroup with an initial value of MCH < 31 pg, the median PFS was 2 months (p = 0.032). Conclusions In our study, we have described functional plasticity of Treg cells, which prevents them from being used as a prognostic marker. The conversion of Treg cells into Th17 can serve as a basis for the development of a new specific immunotherapeutic method in oncology after confirmation in the experiment in vitro. Given the small dataset, the results will need further validation.

Therapeutic administration of bone marrow-derived mesenchymal stromal cells reduces airway inflammation without up-regulating Tregs in experimental asthma.

Prophylactic administration of mesenchymal stromal cells (MSCs) derived from adipose (AD-MSC) and bone marrow tissue (BM-MSC) in ovalbumin-induced asthma hinders inflammation in a Treg-dependent manner. It is uncertain whether MSCs act through Tregs when inflammation is already established in asthma induced by a clinically relevant allergen. Evaluate the effect of therapeutic administration of MSCs on inflammation and Treg cells in house dust mite (HDM)-induced asthma. BM-MSCs and AD-MSCs were administered intratracheally to C57BL/6 mice 1 day after the last HDM challenge. Lung function, remodelling and parenchymal inflammation were assayed 3 or 7 days after MSCs treatment, through invasive plethysmography and histology, respectively. Bronchoalveolar lavage fluid (BALF) and mediastinal lymph nodes (mLNs) were assessed regarding the inflammatory profile by flow cytometry, ELISA and qRT-PCR. MSCs were studied regarding their potential to induce Treg cells from primed and unprimed lymphocytes in vitro. BM-MSCs, but not AD-MSCs, reduced lung influx of eosinophils and B cells and increased IL-10 levels in HDM-challenged mice. Neither BM-MSCs nor AD-MSCs reduced lung parenchymal inflammation, airway hyperresponsiveness or mucus hypersecretion. BM-MSCs and AD-MSCs did not up-regulate Treg cell counts within the airways and mLNs, but BM-MSCs decreased the pro-inflammatory profile of alveolar macrophages. Co-culture of BM-MSCs and AD-MSCs with allergen-stimulated lymphocytes reduced Treg cell counts in a cell-to-cell contact-independent manner, although co-culture of both MSCs with unprimed lymphocytes up-regulated Treg cell counts. MSCs therapeutically administered exert anti-inflammatory effects in the airway of HDM-challenged mice, but do not ameliorate lung function or remodelling. Although MSC pre-treatment can increase Treg cell numbers, it is highly unlikely that the MSCs will induce Treg cell expansion when lymphocytes are allergenically primed in an established lung inflammation.

Activation-induced FOXP3 isoform profile in peripheral CD4+ T cells is associated with coronary artery disease

Background and aimsThe expression of FOXP3 isoforms affects regulatory T (Treg) cell function. Reduced Treg cell function has been associated with coronary artery disease (CAD). However, alternative splicing of FOXP3 in CAD has not been investigated. MethodsFOXP3 splice variants and IL17A transcripts in peripheral blood mononuclear cells from stable CAD patients and healthy controls were quantified, and FOXP3 isoform expression in response to T cell receptor (TCR) stimulation or LDL was analyzed by flow cytometry. ResultsCompared to healthy controls, CAD patients expressed significantly more FOXP3 transcripts that included exon 2, whereas alternative splicing of exon 7 in correlation with IL17A expression was reduced. Moreover, TCR stimulation, as well as exposure to LDL, decreased alternative splicing of FOXP3 in CD4+ T cells in vitro. ConclusionsOur results demonstrate that blood mononuclear cells in stable CAD patients express a ratio of FOXP3 isoforms that is characteristic for activated CD4+ T cells.

Regulatory T cells and IL-10 as modulators of chikungunya disease outcome: a preliminary study.

Regulatory T (Treg) cells hold centre stage in regulating the immune responses in most viral infections. However, their involvement in chikungunya infection is unexplored. In the current study, the frequencies and functionality of peripheral Treg and T effector (Teff) cells were assessed during different phases of chikungunya by flow cytometry and in-vitro cytokine assays. Treg cells were also studied in rheumatoid arthritis (RA) patients, whose symptoms closely mimic chronic chikungunya arthritis patients. Frequency of Treg cells was lower in acute and chronic chikungunya arthritis patients than in recovered individuals and controls, and comparable among recovered individuals and controls. Treg/Teff ratio was lower in acute than in chronic chikungunya arthritis patients, recovered individuals and controls. Higher secretion of CHIKV specific IL-10 was observed in recovered individuals than in acute, chronic chikungunya arthritis patients and controls. Frequencies of Treg and Teff cells were higher and Treg/Teff ratio was lower in RA patients than in chronic chikungunya arthritis patients. The results indicate that reduction of Treg cells was associated with ongoing CHIKV infection and normalization of Treg cells with resolution of disease. Contrasting phenotypic data in RA and chronic chikungunya arthritis suggest an altogether different mechanism of Treg-mediated pathology in both arthritis conditions. Overall, our preliminary study, suggesting an association of peripheral Treg cells and IL-10 with recovery from chikungunya, may provide insight into chikungunya disease prognosis and warrants further study.

NK cells of HIV-1-infected patients with poor CD4+ T-cell reconstitution despite suppressive HAART show reduced IFN-γ production and high frequency of autoreactive CD56bright cells

HIV-1-infected patients failing to recover CD4+ T-cell count despite HAART (immunological non-responders, NRs), are at increased risk of disease progression and death. To better understand the NR status, we performed a comprehensive assessment of NK cells in NR patients as compared to immunologic responders. NRs exhibited an accumulation of CD56bright NK cells inversely correlated with CD4+ counts. Both CD56bright and CD56dim NK cells of NRs displayed unimpaired degranulation ability, but poorly responded to cytokine stimulation in terms of NKp44 up-regulation and IFN-γ production that may explain the susceptibility of NRs to infections and tumors. Notably, CD56bright NK cells from NRs showed higher cytotoxicity against autologous activated CD4+ T cells. Moreover, NRs had reduced Treg cell counts that showed an inverse correlation with autoreactive CD56bright cells. These data suggest that accumulation of CD56bright NK cells, possibly linked to decreased homeostatic control by Tregs, contributes to poor immune reconstitution in NRs.

Skewing toward Treg and Th2 responses is a characteristic feature of sustained remission in ANCA-positive granulomatosis with polyangiitis.

The objective of our study was to evaluate the T-helper (Th) and regulatory T (Treg) cell profile in ANCA-positive granulomatosis with polyangiitis (GPA) and its relation to disease activity. In a prospective study, we studied two groups of GPA patients: (i) disease flare (active-GPA, BVAS>6, n = 19), (ii) sustained remission (≥ 1-year prior enrollment, inactive-GPA, BVAS = 0, n = 18). 24 age-sex matched healthy subjects served as controls. Active-GPA patients were followed for 6 months and reevaluated during remission (early remission; n = 13). We analyzed subsets of Th-cells (flow cytometry), production of signature cytokines by in vitro stimulated lymphocytes, and broad spectrum of serum cytokines (Luminex). In all GPA patients we observed expansion of effector Th17 cells, and increased production of IL-17A by in vitro stimulated T cells, as compared to controls. Disease flare was characterized by marked reduction in Treg cells, whereas in sustained remission we showed expansion of both Treg and Th2 subset. Finally, analyzing the cytokine profile, we identified CCL23 and LIGHT, as potential biomarkers of active disease. We conclude that in GPA, expansion of Treg and Th2 lymphocytes in parallel to increased Th17 response is a characteristic feature of sustained remission. In contrast, Treg cells are markedly decreased in disease flare.

Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model.

Interleukin (IL)-12 is a potent antitumor cytokine. However, immunosuppressive tumor microenvironments containing transforming growth factor-β (TGF-β) attenuate cytokine-mediated antitumor immune responses. To enhance the efficacy of IL-12-mediated cancer immunotherapy, decorin (DCN) was explored as an adjuvant for overcoming TGF-β-mediated immunosuppression. We designed and generated a novel oncolytic adenovirus (Ad) coexpressing IL-12 and DCN (RdB/IL12/DCN). RdB/IL12/DCN-treated tumors showed significantly greater levels of interferon (IFN)-γ, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IFN-γ-secreting immune cells than tumors treated with cognate control oncolytic Ad expressing a single therapeutic gene (RdB/DCN or RdB/IL12). Moreover, RdB/IL12/DCN attenuated intratumoral TGF-β expression, which positively correlated with reduction of Treg cells in draining lymph nodes and tumor tissues. Furthermore, tumor tissue treated with RdB/IL12/DCN showed increases infiltration of CD8+ T cells and proficient viral spreading within tumor tissues. These results demonstrated that an oncolytic Ad co-expressing IL-12 and DCN induces a potent antitumor immune response via restoration of antitumor immune function in a weakly immunogenic murine 4T1 orthotopic breast cancer model. These findings provide new insights into the therapeutic mechanisms of IL-12 plus DCN, making it a promising cancer immunotherapeutic agent for overcoming tumor-induced immunosuppression.

Low regulatory T cell and high IL-17 mRNA expression in a mouse Graves' disease model.

Graves' disease (GD) is an autoimmune thyroid disease, and the most important characteristic of it is the presence of the thyroid-stimulating antibody (TSAb). The mechanisms of the TSAb elevation are still uncertain. Recent studies have suggested that the dysregulation of regulatory T cell (Treg) and T helper 17 (Th17) might stimulate the production of TSAb and be a pathogenesis of GD. However, the role of Treg and Th17 cells in the pathogenesis of GD is still debated. Our aim is to assess changes of Treg and Th17 cells in the spleen of a mouse in an in vivo GD model and try to explain the pathogenesis of GD. We used an adenovirus expressing the autoantigen thyroid-stimulating hormone receptor (Ad-TSHR289) to immunise mice in order to induce GD in the model. Flow cytometry was used to measure the frequencies of splenic Treg and Th17 cells and real-time PCR to analyse the mRNA expression of forkhead box P3(Foxp3) and interleukin-17(IL-17). Compared with the Ad-Control group, the frequencies of CD4+CD25+Foxp3+ Treg cells were significantly decreased (p=0.007) and gene expression of Foxp3 was down-regulated (p=0.001) in the Ad-TSHR289 group. Though there was no significant difference in CD4+IL-17+ T cell subpopulation between the two groups (p=0.336), the IL-17 mRNA expression was significantly up-regulated in the Ad-TSHR289 group (p=0.001). The pathogenesis of GD may be associated with reduced Treg cells and increased IL-17 gene expression. The increased IL-17 mRNA needs to be explained by other mechanisms but not Th17 cells.

FOXP3+ associated with the pro-inflammatory regulatory T and T helper 17 effector cells in asthma patients.

Asthma is a chronic bronchial inflammation that results to reversible incidence of airway obstruction and shortness of breath. Under normal circumstances, the lung immune system is maintained in a state of controlled inflammation, where balance exists between protective immunity mediated by effector cells and tolerance mediated by cells with regulatory function. Therefore, the inflammation observed in asthma patients may be caused by an imbalance between regulatory T (Treg) cells (CD4-positive with high expression of CD25 surface markers) and forkhead box P3 (FOXP3)-positive pro-inflammatory T helper 17 (Th17) cells. The aim of the present study was to evaluate whether reduced Treg cells and increased Th17 cells could be observed in the peripheral blood samples of asthma patients. As important markers of Treg cells, the expression levels of FOXP3 and interleukin (IL)-17a were analyzed via reverse trancription-quantitative polymerase chain reaction. The results indicated that the levels of cytokines that promote Th17 cells, including IL-6, IL-23 and TGF-β, were found to increase in the bronchoalveolar lavage fluid sample of asthma patients. However, the IL-10 level in the corresponding sample was much lower compared with that in control individuals. In conclusion, these results suggest that asthma associated with a reduced proportion of Treg and Th17 cells in the blood is characterized by the expression of pro-inflammatory cytokines that may be beneficial for the continuous generation of Th17 cells.

Highlights of This Issue

Long-term survival is observed in a minority of melanoma patients after treatment with ipilimumab, while the benefit seems to be limited for others. Thus far, no biomarkers are routinely used to predict outcome. In a large multicenter study, Martens and colleagues identified a strong association between baseline frequencies of myeloid-derived suppressor cells and overall survival after start of ipilimumab, translating into a rationale for depletion/inhibition of these cells as therapeutic strategy. Moreover, they propose combination models, including one limited to broadly available routine markers, which strongly correlate with prognosis and suggest predictive impact for outcome after ipilimumab.Next-generation sequencing (NGS) has redefined the genetic landscape of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. To explore the feasibility of NGS in routine DLBCL patient management, Dubois and colleagues designed the Lymphopanel, a targeted panel based on 34 genes, with a distinct focus on the inclusion of actionable and prognostic targets. The Lymphopanel was informative for 96% of DLBCL patients and offered a clear depiction of DLBCL subtype molecular heterogeneity. The Lymphopanel is a clinically feasible tool, which can stratify patients according to their mutational profiles to afford novel personalized therapy opportunities.The immune checkpoint inhibitors (ICI) are proven to be effective in cancer immunotherapy; however, the efficacy may be further improved. Ma and colleagues examined the therapeutic effect of a combination of IL18 with ICIs using an animal model of disseminated tumor growth. The results showed that the combination markedly augmented the therapeutic effect. Notably, strong expansion of effector cells, including NK cells and CD8+ T cells, and reduction of Treg cells in the tumor microenvironments were observed. There was apparently no adverse effect augmented by the combination. The combination of IL18 and ICIs may be beneficial for cancer immunotherapy.To build on recent successes in cancer immunotherapy, we need to better understand how the immune system normally contends with cancer. Although the prognostic benefit of tumor-infiltrating T cells is well established, Kroeger and colleagues use innovative immunohistochemical analyses to reveal an equally important role for plasma cells (mature antibody-producing cells) in ovarian cancer. Remarkably, the authors found that the prognostic benefit of T cells is only seen in the presence of plasma cells, suggesting critical interactions between these lymphocyte subsets. The goal now is to develop immunotherapies that promote this potent combination of cellular and humoral responses in patients.

Regulatory T-Cell Plasticity

During the past 2 decades, human and animals studies have clearly documented the crucial role of inflammation in the development and complications of atherosclerosis.1 Both innate immunity and adaptive immunity are involved in this process. The first evidence that suggested a role of adaptive immunity in atherosclerosis was the widespread detection of the major histocompatibility class II in human atherosclerotic plaques and the presence of a large amount of CD3+ lymphocytes in human and mouse atherosclerotic lesions. Most of the T cells in mouse and human atherosclerotic plaques are CD4+ T-helper (Th) cells expressing the αβ T-cell antigen receptor. Among CD4+ T cells, Th1 cells have been shown to exert proatherogenic effects, whereas regulatory T cells (Tregs) display atheroprotective properties. The role of Th2 and Th17 cells is still debated.1 Helper T-cell subsets are defined by the production of cytokines or the expression of characteristic lineage-defining transcription factors. Th1 cells are generated on priming in the presence of interleukin (IL)-12 that promotes the expression of the transcription factor T-bet and stimulates the production of the Th1 prototypical cytokine interferon-γ (IFN-γ).2 Tregs have a central role in the dominant control of immunologic tolerance and maintenance of immune homeostasis. They were first identified in mice and later in humans.3 The transcription factor FoxP3 is essential for the generation and the functions of Tregs.4 FoxP3 deficiency leads to a multiorgan autoimmune disease as can be observed in the scurfy mouse and in human immune dysregulation, polyendocrinopathy, enteropathy X–linked syndrome patients.5 Natural or thymic FoxP3+ Tregs acquire regulatory lineage commitment already on maturation in the thymus,3 whereas adaptive or peripheral FoxP3+ Tregs can be induced from mature CD4+ Th cells in the periphery under the influence of different stimulations, especially transforming …

Control of TH17 and Treg balance by RhoGTPase Cdc42

Abstract Balanced Th17 and regulatory T (Treg) cell differentiation and function are important for normal immunity and avoidance of autoimmunity. Cdc42 of the Rho GTPase family is an intracellular signal transducer that cycles between an inactive GDP- bound form and an active GTP-bound form under tight regulation. We have recently reported that Cdc42 is required for thymocyte development but suppresses Th1 cell differentiation, with no effect on Th2 cells. In this study, we further examined the role of Cdc42 in Th17 and Treg cell differentiation, using a T cell-specific Cdc42 conditional knockout mouse model. Cdc42 deficiency led to an enhanced Th17 differentiation evidenced by increased IL-17+ cells with increased STAT3 phosphorylation, under in vitro Th17 polarizing condition. In the absence of Cdc42, Foxp3+ cells were drastically reduced under in vitro Treg polarizing condition accompanied by less phosphorylation of Smad2 and Smad3 transcription factors. Functionally, in vitro Treg suppression assay found that Cdc42-deficient Treg cells were impaired in their suppressive activity. In both DSS induced colitis and naïve T cell transfer model of colitis in vivo, Cdc42 deficiency led to an exacerbated disease severity and increased infiltration of Th17 and Th1 cells with less Tregs in spleen, mLN and lamina propria of colon. Finally, Treg cell-specific deletion of Cdc42 resulted in systemic autoimmunity with reduced Treg cells and accordingly spontaneous T cell activation and increased IL-17+IFNγ+ double positive cells. In summary, our data have provided new insights into the regulation of the balance between Th17 and Treg differentiation and identified Cdc42 as a potential molecular target for the treatment of colitis.

Suppressor of cytokine signaling 2 modulates the immune response profile and development of experimental cerebral malaria

Plasmodium falciparum infection results in severe malaria in humans, affecting various organs, including the liver, spleen and brain, and resulting in high morbidity and mortality. The Plasmodium berghei ANKA (PbA) infection in mice closely recapitulates many aspects of human cerebral malaria (CM); thus, this model has been used to investigate the pathogenesis of CM. Suppressor of cytokine signaling 2 (SOCS2), an intracellular protein induced by cytokines and hormones, modulates the immune response, neural development, neurogenesis and neurotrophic pathways. However, the role of SOCS2 during CM remains unknown. SOCS2 knockout (SOCS2−/−) mice infected with PbA show an initial resistance to infection with reduced parasitemia and production of TNF, TGF-β, IL-12 and IL-17 in the brain. Interestingly, in the late phase of infection, SOCS2−/− mice display increased parasitemia and reduced Treg cell infiltration, associated with enhanced levels of Th1 and Th17 cells and related cytokines IL-17, IL-6, and TGF-β in the brain. A significant reduction in protective neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was also observed. Moreover, the molecular alterations in the brain of infected SOCS2−/− mice were associated with anxiety-related behaviors and cognition impairment. Mechanistically, these results revealed enhanced nitric oxide (NO) production in PbA-infected SOCS2−/− mice, and the inhibition of NO synthesis through l-NAME led to a marked decrease in survival, the disruption of parasitemia control and more pronounced anxiety-like behavior. Treatment with l-NAME also shifted the levels of Th1, Th7 and Treg cells in the brains of infected SOCS2−/− mice to the background levels observed in infected WT, with remarkable exception of increased CD8+IFN+ T cells and inflammatory monocytes. These results indicate that SOCS2 plays a dual role during PbA infection, being detrimental in the control of the parasite replication but crucial in the regulation of the immune response and production of neurotrophic factors. Here, we provided strong evidence of a critical relationship between SOCS2 and NO in the orchestration of the immune response and development of CM during PbA infection.

Research Progress on role of Abnormal Tryptophan Metabolism in Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is a common acquired autoimmune hematological disorders. Platelet autoantibodies lead to the decrease of platelet production and (or) increase of its destruction. The latest researches showed that the abnormal tryptophan metabolism mediated by indoleamine-2, 3-dioxygenase(IDO) is related with the pathogenesis of ITP. The patients with ITP show less expression of IDO, reduction of Treg cells and increase of autoreactive T cells and autoantibodies. CTLA-4-Ig can improve the expression of IDO in the patients with ITP, which also can inhibit the proliferation and activation of self-reactive T cells. Thus, clarifying the abnormal tryptophan metabolism mediated by IDO may provide a new idea for improving the understand of the pathogenesis and treatment of ITP. This review focuses on reasearch progress of the tryptophan metabolism mediated by IDO and ITP.

Lactobacillus rhamnosus GG supernatant promotes intestinal barrier function, balances Treg and TH17 cells and ameliorates hepatic injury in a mouse model of chronic-binge alcohol feeding.

Impaired intestinal barrier function plays a critical role in alcohol-induced hepatic injury, and the subsequent excessive absorbed endotoxin and bacterial translocation activate the immune response that aggravates the liver injury. Lactobacillus rhamnosus GG supernatant (LGG-s) has been suggested to improve intestinal barrier function and alleviate the liver injury induced by chronic and binge alcohol consumption, but the underlying mechanisms are still not clear. In this study, chronic-binge alcohol fed model was used to determine the effects of LGG-s on the prevention of alcoholic liver disease in C57BL/6 mice and investigate underlying mechanisms. Mice were fed Lieber-DeCarli diet containing 5% alcohol for 10 days, and one dose of alcohol was gavaged on Day 11. In one group, LGG-s was supplemented along with alcohol. Control mice were fed isocaloric diet. Nine hours later the mice were sacrificed for analysis. Chronic-binge alcohol exposure induced an elevation in liver enzymes, steatosis and morphology changes, while LGG-s supplementation attenuated these changes. Treatment with LGG-s significantly improved intestinal barrier function reflected by increased mRNA expression of tight junction (TJ) proteins and villus-crypt histology in ileum, and decreased Escherichia coli (E. coli) protein level in liver. Importantly, flow cytometry analysis showed that alcohol reduced Treg cell population while increased TH17 cell population as well as IL-17 secretion, which was reversed by LGG-s administration. In conclusion, our findings indicate that LGG-s is effective in preventing chronic-binge alcohol exposure-induced liver injury and shed a light on the importance of the balance of Treg and TH17 cells in the role of LGG-s application.

CD36 deficiency blunts effects of diet on regulatory T cells in murine gonadal adipose tissue and mesenteric lymph nodes

The effect of cluster of differentiation (CD)36 on regulatory T cells (Treg) was investigated in gonadal (GN) adipose tissues and mesenteric lymph nodes (MLN) of wild-type (WT) and CD36 deficient (CD36−/−) mice kept on standard fat (SFD, lean) or on high fat diet (HFD, obese). GN adipose tissue mass was smaller, but MLN size larger for obese CD36−/− versus obese WT mice. Overall, the reduction of Treg cells in GN adipose tissue and MLN after a HFD is much more prominent in WT than CD36−/− mice. Moreover, CD36−/− mice may be protected against obesity-related chronic inflammation.

Anti-CCR4 antibody activates virus specific immune response in STLV-1 infected Japanese monkey

Transgenic mouse model is useful to study pathogenesis of viral genes like tax and HBZ. However, it is impossible to study the host immune responses by these transgenic mice. We used simian T-cell leukemia virus type 1 (STLV-1) infected Japanese monkeys (JMs) to analyze host immune responses after treatment by anti-CCR4 monoclonal antibody (mAb). In the previous study, we reported that anti-CCR4 mAb treatment in STLV-1 infected JMs significantly reduced CCR4 positive cells and STLV-1 proviral load (PVL). In this study, we investigated the long-term effect (48 weeks) on PVL and immune responses to STLV-1 Tax (sTax) and bZIP factor (SBZ) after the anti-CCR4 mAb treatment. STLV-1 PVL in the JMs was kept at the lower level than 0 week even 48 weeks later. To further investigate the antiCCR4 mAb induced antiviral effect, we analyzed regulatory T (Treg) cells and sTax and SBZ specific T-cell responses. Treg cells, which were CCR4 positive, were rapidly reduced after the treatment. The number of activated Treg cells (most functional population) was severely suppressed. Furthermore, anti-CCR4 mAb treatment of infected CD4 T cells from the JMs enhanced engulfment by phagocytes, which likely enhances antigen-presentation. Treated JMs showed spontaneous activation of cytotoxic T-lymphocytes (CTLs) to sTax and SBZ. However, the immune response to other antigen was not enhanced. In consistent with these data, the enhanced T-cell responses (anti-Tax and HBZ) were also observed in anti-CCR4 mAb treated ATL patients. Taken together, anti-CCR4 mAb induces CTLs to sTax/Tax and HBZ/SBZ by two different mechanisms: reduced Treg cells and enhanced antigen presentation by antibodydependent cell-mediated phagocytosis. These effects of anti-CCR4 mAb induce prolonged suppression of PVL, which might enable long-term control of ATL and HTLV-1 infected cells.