Clinical Significance of Myeloid-Derived Suppressor Cells in Human Renal Transplantation with Acute T Cell-Mediated Rejection

Myeloid-derived suppressor cells (MDSCs) are negative regulators of the immune response and are in part responsible for the inhibition of the T cell-mediated immune response. A recent paper indicated that MDSCs were involved in prolonged allograft survival in animal models of transplantation, but the significance of MDSCs in human renal transplantation is still unknown. In our study, 50 patients with biopsy-proven acute T cell-mediated rejection (ATCMR) were included. The ratio of MDSCs in peripheral blood mononuclear cell (PBMC) was evaluated with FACS, and the patients were divided into the MDSCs high group (MDSCs, >10 %) or the MDSCs low group (MDSCs, <10 %). We compared the allograft function, severity of tissue injury, and long-time survival between the two groups. In the MDSCs high group, allograft function was significantly increased compared with the MDSCs low group. Furthermore, we found that isolated MDSCs from transplant recipients are capable of expanding regulatory T cell (Treg), meanwhile, inhibiting production of IL-17 in vitro. We also found that the ratio between Foxp3⁺ and IL-17-producing CD4⁺ T cells positively correlated with MDSCs frequency in PBMC. In conclusion, we demonstrated a potential role for MDSCs in prolonging allograft survival after ATCMR, and this was associated with higher CD4⁺Foxp3⁺/CD4⁺IL-17⁺ ratio in PBMC.     

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8+ T cells

Immune responses to protein antigens involve CD4⁺ and CD8⁺ T cells, which follow distinct programs of differentiation. Naïve CD8 T cells rapidly develop cytotoxic T‐cell (CTL) activity after T‐cell receptor stimulation, and we have previously shown that this is accompanied by suppressive activity in the presence of specific cytokines, i.e. IL‐12 and IL‐4. Cytokine‐induced CD8⁺ regulatory T (Treg) cells are one of several Treg‐cell phenotypes and are Foxp3^? IL‐10⁺ with contact‐dependent suppressive capacity. Here, we show they also express high level CD39, an ecto‐nucleotidase that degrades extracellular ATP, and this contributes to their suppressive activity. CD39 expression was found to be upregulated on CD8⁺ T cells during peripheral tolerance induction in vivo, accompanied by release of IL‐12 and IL‐10. CD39 was also upregulated during respiratory tolerance induction to inhaled allergen and on tumor‐infiltrating CD8⁺ T cells. Production of IL‐10 and expression of CD39 by CD8⁺ T cells was independently regulated, being respectively blocked by extracellular ATP and enhanced by an A2A adenosine receptor agonist. Our results suggest that any CTL can develop suppressive activity when exposed to specific cytokines in the absence of alarmins. Thus negative feedback controls CTL expansion under regulation from both nucleotide and cytokine environment within tissues.     

Glatiramer acetate ameliorates inflammatory bowel disease in mice through the induction of Qa‐1‐restricted CD8+ regulatory cells

Inflammatory bowel diseases (IBDs) are complex multifactorial immunological disorders characterized by dysregulated immune reactivity in the intestine. Here, we investigated the contribution of Qa‐1‐restricted CD8⁺ Treg cells in regulating experimental IBD in mice. We found that CD8⁺ T cells induced by T‐cell vaccination ameliorated the pathological manifestations of dextran sulfate sodium induced IBD when adoptively transferred into IBD mice. In addition, CD8⁺ cell suppressive activity was induced by vaccination with glatiramer acetate (GA), an FDA‐approved drug for multiple sclerosis (MS). We next showed that GA‐induced CD8⁺ Treg cells worked in a Qa‐1‐dependent manner and their suppressive activity depends on perforin‐mediated cytotoxicity. Finally, we confirmed the role of CD4⁺ T cells in dextran sulfate sodium induced colitis progression, and clarified that GA‐induced CD8⁺ T cells exerted their therapeutic effects on colitis by targeting pathogenic CD4⁺ T cells. Our results reveal a new regulatory role of Qa‐1‐restricted CD8⁺ Treg cells in IBD and suggest their induction by GA vaccination as a potential therapeutic approach to IBD.     

CD73 expression on extracellular vesicles derived from CD4+CD25+Foxp3+ T cells contributes to their regulatory function

CD4⁺CD25⁺Foxp3⁺ Treg cells maintain immunological tolerance. In this study, the possibility that Treg cells control immune responses via the production of secreted membrane vesicles, such as exosomes, was investigated. Exosomes are released by many cell types, including T cells, and have regulatory functions. Indeed, TCR activation of both freshly isolated Treg cells and an antigen‐specific Treg‐cell line resulted in the production of exosomes as defined morphologically by EM and by the presence of tetraspanin molecules LAMP‐1/CD63 and CD81. Expression of the ecto‐5‐nucleotide enzyme CD73 by Treg cells has been shown to contribute to their suppressive function by converting extracellular adenosine‐5‐monophosphate to adenosine, which, following interaction with adenosine receptors expressed on target cells, leads to immune modulation. CD73 was evident on Treg cell derived exosomes, accordingly when these exosomes were incubated in the presence of adenosine‐5‐monophosphate production of adenosine was observed. Most importantly, CD73 present on Treg cell derived exosomes was essential for their suppressive function hitherto exosomes derived from a CD73‐negative CD4⁺ T‐cell line did not have such capabilities. Overall our findings demonstrate that CD73‐expressing exosomes produced by Treg cells following activation contribute to their suppressive activity through the production of adenosine.     

VEGFR2 is selectively expressed by FOXP3high CD4+ Treg

CD25⁺ FOXP3⁺CD4⁺ T cells (Treg) have been considered to play an important role in immune tolerance against several tumor antigens. It has also been indicated that high‐level expression of FOXP3 (FOXP3^high) is sufficient to confer suppressive activity to normal non‐Treg. Here, we showed for the first time that vascular endothelial growth factor receptor 2 (VEGFR2) is selectively expressed by FOXP3^high but not FOXP3^low Treg. Such VEGFR2⁺ Treg exist in several tissues including PBMC and malignant effusion‐derived lymphocytes. In conclusion, VEGFR2 may be a novel target for controlling Treg with highly suppressive function.     

Blood immune cell biomarkers in lung cancer

Characterization of host immune cell parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. We monitored blood immune cells from 58 patients with non-small- cell lung cancer (NSCLC) undergoing surgery of the primary tumor and from 50 age-matched healthy volunteers. Complete leukocyte blood count, the number of circulating dendritic cells (DC), HLA-DR^low monocytes and several lymphocytic subpopulations were determined by eight-color flow cytometry. Furthermore, the prognostic value of the immune cell parameters investigated was evaluated by patients’ survival analysis. Compared to the control group, blood of NSCLC patients contained more neutrophils resulting in a higher neutrophil-to-lymphocyte ratio (NLR), but a lower number of blood DC, in particular of plasmacytoid DC (pDC), natural killer (NK) cells and naive CD4⁺ and CD8⁺ T cells. Furthermore, a higher frequency of CD4⁺ regulatory T cells (Treg) and HLA-DR^low monocytes was detected, and smoking had a significant impact on these values. HLA-DR^low monocytes were positively correlated to the number of neutrophils, monocytes and NLR, but negatively associated with the number of pDC and naive CD4⁺ T cells. The frequency of Treg, HLA-DR^low monocytes and naive CD4⁺ and CD8⁺ T cells as well as the ratios of CD4/HLA-DR^low monocytes and HLA-DR^low monocytes/pDC correlated with patient’s overall survival. Next to Treg, HLA-DR^low monocytes and naive T cells represent prognostic markers for NSCLC patients and might be useful for monitoring of patients’ responses to immunotherapies in future studies.     

Human retinal pigment epithelium-induced CD4CD25 regulatory T cells suppress activation of intraocular effector T cells

Murine retinal pigment epithelial (RPE) cells suppress T-cell activation by releasing soluble inhibitory factors and promote the generation of regulatory T cells in vitro. These T cells exposed to RPE supernatants (RPE-induced Treg cells) can suppress the activation of bystander effector T cells via the production of transforming growth factor-beta (TGFβ). In the present study, we showed that human RPE-induced Treg cells are also able to acquire regulatory function when human RPE cell lines were pretreated with recombinant TGFβ2. These RPE-induced Treg cells produced TGFβ1 and IL-10 but not IFNγ, and they significantly suppressed the activation of target cell lines and intraocular T-cell clones established from patients with active uveitis. Moreover, CD4⁺CD25⁺ RPE-induced Treg cells expressed CTLA-4 and Foxp3 molecules, and the CD25⁺ Treg cells profoundly suppressed the T-cell activation. Thus, in vitro manipulated Treg cells acquire functions that participate in the establishment of immune tolerance in the eye.     

Mouse and human CD8+ CD28low regulatory T lymphocytes differentiate in the thymus

Regulatory T (Treg) lymphocytes play a central role in the control of immune responses and so maintain immune tolerance and homeostasis. In mice, expression of the CD8 co‐receptor and low levels of the co‐stimulatory molecule CD28 characterizes a Treg cell population that exerts potent suppressive function in vitro and efficiently controls experimental immunopathology in vivo. It has remained unclear if CD8⁺ CD28^low Treg cells develop in the thymus or represent a population of chronically activated conventional T cells differentiating into Treg cells in the periphery, as suggested by their CD28^low phenotype. We demonstrate that functional CD8⁺ CD28^low Treg cells are present in the thymus and that these cells develop locally and are not recirculating from the periphery. Differentiation of CD8⁺ CD28^low Treg cells requires MHC class I expression on radioresistant but not on haematopoietic thymic stromal cells. In contrast to other Treg cells, CD8⁺ CD28^low Treg cells develop simultaneously with CD8⁺ CD28^high conventional T cells. We also identified a novel homologous naive CD8⁺ CD28^low T‐cell population with immunosuppressive properties in human blood and thymus. Combined, our data demonstrate that CD8⁺ CD28^low cells can develop in the thymus of mice and suggest that the same is true in humans.     

Continuous activation of polymorphonuclear myeloid-derived suppressor cells during pregnancy is critical for fetal development

The maternal immune system is vital in maintaining immunotolerance to the semiallogeneic fetus for a successful pregnancy. Although studies have shown that myeloid-derived suppressor cells (MDSCs) play an important role in maintaining feto-maternal tolerance, little is known about the role of MDSCs in pregnancies with intrauterine growth retardation (IUGR). Here, we reported that the activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) during pregnancy was closely associated with fetal growth. In humans, class E scavenger receptor 1 (SR-E1), a distinct marker for human PMN-MDSCs, was used to investigate PMN-MDSC function during pregnancy. Continuous activation of SR-E1⁺ PMN-MDSCs was observed in all stages of pregnancy, accompanied by high cellular levels of ROS and arginase-1 activity, mediated through STAT6 signaling. However, SR-E1⁺ PMN-MDSCs in pregnancies with IUGR showed significantly lower suppressive activity, lower arginase-1 activity and ROS levels, and decreased STAT6 phosphorylation level, which were accompanied by an increase in inflammatory factors, compared with those in normal pregnancies. Moreover, the population of SR-E1⁺ PMN-MDSCs was negatively correlated with the adverse outcomes of newborns from pregnancies with IUGR. In mice, decreases in cell population, suppressive activity, target expression levels, and STAT6 phosphorylation levels were also observed in the pregnancies with IUGR compared with the normal pregnancies, which were rescued by the adoptive transfer of PMN-MDSCs from pregnant mice. Interestingly, the growth-promoting factors (GPFs) secreted by placental PMN-MDSCs in both humans and mice play a vital role in fetal development. These findings collectively support that PMN-MDSCs have another new role in pregnancy, which can improve adverse neonatal outcomes.     

CD122+CD8+ Treg suppress vaccine‐induced antitumor immune responses in lymphodepleted mice

Lymphodeleption prior to adoptive transfer of tumor‐specific T cells greatly improves the clinical efficacy of adoptive T‐cell therapy for patients with advanced melanoma, and increases the therapeutic efficacy of cancer vaccines in animal models. Lymphodepletion reduces competition between lymphocytes, and thus creates “space” for enhanced expansion and survival of tumor‐specific T cells. Within the lymphodepleted host, Ag‐specific T cells still need to compete with other lymphocytes that undergo lymphopenia‐driven proliferation. Herein, we describe the relative capacity of naïve T cells, Treg, and NK cells to undergo lymphopenia‐driven proliferation. We found that the major population that underwent lymphopenia‐driven proliferation was the CD122⁺ memory‐like T‐cell population (CD122⁺CD8⁺ Treg), and these cells competed with Ag‐driven proliferation of melanoma‐specific T cells. Removal of CD122⁺CD8⁺ Treg resulted in a greater expansion of tumor‐specific T cells and tumor infiltration of functional effector/memory T cells. Our results demonstrate the lymphopenia‐driven proliferation of CD122⁺CD8⁺ Treg in reconstituted lymphodepleted mice limited the antitumor efficacy of DC vaccination in conjunction with adoptive transfer of tumor‐specific T cells.     

Depletion of tumor‐induced Treg prior to reconstitution rescues enhanced priming of tumor‐specific,therapeutic effector T cells in lymphopenic hosts

We reported previously that vaccination of reconstituted, lymphopenic mice resulted in a higher frequency of tumor‐specific effector T cells with therapeutic activity than vaccination of normal mice. Here, we show that lymphopenic mice reconstituted with spleen cells from tumor‐bearing mice (TBM), a situation that resembles the clinical condition, failed to generate tumor‐specific T cells with therapeutic efficacy. However, depletion of CD25⁺ Treg from the spleen cells of TBM restored tumor‐specific priming and therapeutic efficacy. Adding back TBM CD25⁺ Treg to CD25^? naïve and TBM donor T cells prior to reconstitution confirmed their suppressive role. CD25⁺ Treg from TBM prevented priming of tumor‐specific T cells since subsequent depletion of CD4⁺ T cells did not restore therapeutic efficacy. This effect may not be antigen‐specific as three histologically distinct tumors generated CD25⁺ Treg that could suppress the T‐cell immune response to a melanoma vaccine. Importantly, since ex vivo depletion of CD25⁺ Treg from TBM spleen cells prior to reconstitution and vaccination fully restored the generation of therapeutic effector T cells, even in animals with established tumor burden, we have initiated a translational clinical trial of this strategy in patients with metastatic melanoma.     

β‐Glucan enhances antitumor immune responses by regulating differentiation and function of monocytic myeloid‐derived suppressor cells

Myeloid‐derived suppressor cells (MDSCs) accumulate in tumor‐bearing hosts and play a major role in tumor‐induced immunosuppression, which hampers effective immuno‐therapeutic approaches. β‐Glucans have been reported to function as potent immuno‐modulators to stimulate innate and adaptive immune responses, which contributes to their antitumor property. Here, we investigated the effect of particulate β‐glucans on MDSCs and found that β‐glucan treatment could promote the differentiation of M‐MDSCs (monocytic MDSCs) into a more mature CD11c⁺ F4/80⁺ Ly6C^low population via dectin‐1 pathway in vitro, which is NF‐κB dependent, and the suppressive function of M‐MDSCs was significantly decreased. Treatment of orally administered yeast‐derived particulate β‐glucan drastically downregulated MDSCs but increased the infiltrated DCs and macrophages in tumor‐bearing mice, thus eliciting CTL and Th1 responses, inhibiting the suppressive activity of regulatory T cells, thereby leading to the delayed tumor progression. We show here for the first time that β‐glucans induce the differentiation of MDSCs and inhibit the regulatory function of MDSCs, therefore revealing a novel mechanism for β‐glucans in immunotherapy and suggesting their potential clinical benefit.     

CD4+CD25+ Treg induction by an HSP60‐derived peptide SJMHE1 from Schistosoma japonicum is TLR2 dependent

Chronic schistosome infection results in the suppression of host immune responses, allowing long‐term schistosome survival and restricting pathology. Current theories suggest that Treg play an important role in this regulation. However, the mechanism of Treg induction during schistosome infection is still unknown. The aim of this study was to determine the mechanism behind the induction of CD4⁺CD25⁺ T cells by Schistosoma japonicum HSP60 (SjHSP60)‐derived peptide SJMHE1 as well as to elucidate the cellular and molecular basis for the induction of CD4⁺CD25⁺ T cells during S. japonicum infection. Mice immunized with SJMHE1 or spleen and LN cells from naïve mice pretreated with SJMHE1 in vitro all displayed an increase in CD4⁺CD25⁺ T‐cell populations. Release of IL‐10 and TGF‐β by SJMHE1 stimulation may contribute to suppression. Adoptively transferred SJMHE1‐induced CD4⁺CD25⁺ T cells inhibited delayed‐type hypersensitivity in BALB/c mice. Additionally, SJMHE1‐treated APC were tolerogenic and induced CD4⁺ cells to differentiate into suppressive CD4⁺CD25⁺ Treg. Furthermore, our data support a role for TLR2 in SJMHE1‐mediated CD4⁺CD25⁺ Treg induction. These findings provide the basis for a more complete understanding of the S. japonicum–host interactions that contribute to host homeostatic mechanisms, preventing an excessive immune response.     

Human antigen‐specific CD4+CD25+CD134+CD39+ T cells are enriched for regulatory T cells and comprise a substantial proportion of recall responses

Human Ag‐specific CD4⁺ T cells can be detected by their dual expression of CD134 (OX40) and CD25 after a 44 hours stimulation with cognate Ag. We show that surface expression of CD39 on Ag‐specific cells consistently identifies a substantial population of CD4⁺CD25⁺CD134⁺CD39⁺ T cells that have a Treg‐cell‐like phenotype and mostly originate from bulk memory CD4⁺CD45RO⁺CD127^lowCD25^highCD39⁺ Treg cells. Viable, Ag‐specific CD25⁺CD134⁺CD39⁺ T cells could be expanded in vitro as cell lines and clones, and retained high Forkhead Box Protein 3, CTLA‐4 and CD39 expression, suppressive activity and Ag specificity. We also utilised this combination of cell surface markers to measure HIV‐Gag responses in HIV⁺ patients before and after anti‐retroviral therapy (ART). Interestingly, we found that the percentage of CD39^? cells within baseline CD4⁺ T‐cell responses to HIV‐Gag was negatively correlated with HIV viral load pre‐ART and positively correlated with CD4⁺ T‐cell recovery over 96 weeks of ART. Collectively, our data show that Ag‐specific CD4⁺CD25⁺CD134⁺CD39⁺ T cells are highly enriched for Treg cells, form a large component of recall responses and maintain a Treg‐cell‐like phenotype upon in vitro expansion. Identification and isolation of these cells enables the role of Treg cells in memory responses to be further defined and provides a development pathway for novel therapeutics.     

Increased frequency and suppressive activity of CD127low/− regulatory T cells in the peripheral circulation of patients with head and neck squamous cell carcinoma are associated with advanced stage and nodal involvement

The presence of regulatory T (Treg) cells is thought to be an important mechanism by which head and neck squamous cell carcinoma (HNSCC) successfully evades the immune system. Using multicolour flow cytometry, the frequency and functional capacity of two CD4⁺ CD127^low/− Treg cell populations, separated on the basis of different levels of CD25 expression (CD25^inter and CD25^high), from the peripheral circulation of newly presenting HNSCC patients were assessed with regard to clinicopathological features and healthy controls. The frequency of circulating Treg cells was similar between HNSCC patients and healthy controls, and for patients with HNSCC developing from different subsites (laryngeal compared with oropharyngeal). However, patients with advanced stage tumours and those with nodal involvement had significantly elevated levels of CD4⁺ CD25^high CD127^low/− Treg cells compared with patients who had early stage tumours (P = 0·03) and those without nodal involvement (P = 0·03), respectively. CD4⁺ CD25^high CD127^low/− Treg cells from the entire HNSCC patient cohort and from patients whose tumours had metastasized to the lymph nodes were also shown to suppress the proliferation of effector T cells significantly more, compared with those from healthy controls (P = 0·04) or patients with no nodal involvement (P = 0·04). Additionally, CD4⁺ CD25^inter CD127^low/− Treg cells consistently induced greater suppressive activity than CD4⁺ CD25^high CD127^low/− Treg cells on the proliferation of the effector T-cell populations (CD4⁺ CD25⁻ CD127^−/+ and CD4⁺ CD25⁺ CD127⁺). Peripheral Treg cells, identified by the CD127^low/− phenotype, have been shown to be influenced by a patient''s tumour stage and/or nodal status in HNSCC; suggesting a role in tumour progression that could be manipulated by future immunotherapy.     

Expansion of regulatory T cells from umbilical cord blood and adult peripheral blood CD4+CD25+ T cells

CD4⁺CD25⁺ regulatory T cells (Treg), if properly expanded from umbilical cord blood (UCB), may provide a promising immunotherapeutic tool. Our previous data demonstrated that UCB CD4⁺CD25⁺ T cells with 4-day stimulation have comparable phenotypes and suppressive function to that of adult peripheral blood (APB) CD4⁺CD25⁺ T cells. We further examined whether 2-week culture would achieve higher expansion levels of Tregs. UCB CD4⁺CD25⁺ T cells and their APB counterparts were stimulated with anti-CD3/anti-CD28 in the presence of IL-2 or IL-15 for 2 weeks. The cell proliferation and forkhead box P3 (FoxP3) expression were examined. The function of the expanded cells was then investigated by suppressive assay. IL-21 was applied to study whether it counteracts the function of UCB and APB CD4⁺CD25⁺ T cells. The results indicate that UCB CD4⁺CD25⁺ T cells expanded much better than their APB counterparts. IL-2 was superior to expand UCB and APB Tregs for 2 weeks than IL-15. FoxP3 expression which peaked on Day 10–14 was comparable. Most importantly, expanded UCB Tregs showed greater suppressive function in allogeneic mixed lymphocyte reaction. The addition of IL-21, however, counteracted the suppressive function of expanded UCB and APB Tregs. The results support using UCB as a source of Treg cells.     

Avian CD4CD25 regulatory T cells: Properties and therapeutic applications

Regulatory T cells (Tregs) are a subset of T cells that specialize in immune suppression. CD4⁺CD25⁺FoxP3⁺ T cells have been characterized as Tregs and extensively studied in mammals. In the absence of a putative FoxP3 ortholog in avians, CD4⁺CD25⁺ cells is characterized as Tregs in avians. Avian CD4⁺CD25⁺ cells produce high amounts of IL-10, TGF-β, CTLA-4, and LAG-3 mRNA; lack IL-2 mRNA; and suppress T cell proliferation in vitro through both contact-dependent and -independent pathways. Depleting avian CD4⁺CD25⁺ cells increases the proliferation of, IL-2 amount, and IFNγ mRNA amount of CD4⁺CD25⁻ cells. Avian CD4⁺CD25⁺ cells lose their suppressive properties immediately after inflammation and acquire supersuppressive properties once inflammation subsides. Although Treg activity could be beneficial to the host, Tregs simultaneously inhibit host immunity and cause persistent infections of certain pathogens. Therapy targeted toward alleviating Treg mediated immune suppression can improve host immunity against those persistent pathogens and benefit poultry production.     

Myeloid-derived suppressor cells expansion is closely associated with disease severity and progression in HBV-related acute-on-chronic liver failure

Dysregulation of the host immune responses induced by host hepatitis B virus (HBV) interactions has been observed in acute-on-chronic liver failure (ACLF). Myeloid-derived suppressor cells (MDSCs), well known for their immunomodulatory properties, can suppress T-cell function by regulating the expression of CD3 ζ chain in cancer and autoimmune/infectious diseases while rarely have been studied in ACLF. In this study, MDSCs, CD4⁺/CD8⁺ T cells, and CD3 ζ chain were analyzed by flow cytometry in peripheral blood mononuclear cells obtained from HBV-related ACLF patients, chronic hepatitis B (CHB) patients and healthy controls. ACLF patients were followed up for dynamic detection of MDSCs and observation of outcomes after treatment. Interestingly, peripheral CD14⁺CD33⁺CD11b⁺HLA-DR^−/low MDSCs from ACLF patients were significantly increased compared to those from CHB patients and healthy controls. CD4⁺/CD8⁺ T cell frequency and CD3 ζ chain expression in T cells were decreased in ACLF patients compared to those of healthy controls and were negatively correlated with matched MDSC frequency. Meanwhile, the frequency of MDSCs was closely correlated with biochemical parameters that are relevant for liver injury rather than virological parameters. Moreover, a lower level of MDSCs was correlated with a better short-term prognosis (within 4 weeks but not at 8 weeks), and MDSCs remained high in ACLF patients whose conditions worsened within a 4-week follow-up period after treatment. These results suggest that MDSCs are closely involved in cell-mediated immunity in HBV-related ACLF and that peripheral MDSC expansion is closely associated with disease severity and progression in HBV-related ACLF, which may serve as a predictor of short-term prognosis.     

The impact of fingolimod on Treg function in brain ischaemia

Fingolimod has generally shown neuroprotective effects in stroke models. Here, we tested the hypothesis that fingolimod modulates T-cell cytokine production towards a regulatory phenotype. Second, we investigated how fingolimod altered the Treg suppressive function and the sensitivity of effector T cells to regulation. Mice that had underwent the permanent electrocoagulation of the left middle cerebral artery received saline or fingolimod (0.5 mg/kg) daily for 10-days post-ischaemia. Fingolimod improved neurobehavioural recovery compared to saline control and increased Treg frequency in the periphery and brain. Tregs from fingolimod-treated animals had a higher expression of CCR8. Fingolimod increased the frequencies of CD4⁺IL-10⁺, CD4⁺ IFN-γ⁺ and CD4⁺IL-10⁺IFN-γ⁺ cells in spleen and blood, and CD4⁺ IL-17⁺ cells in the spleen, with only minor effects on CD8⁺ T-cell cytokine production. Treg from post–ischaemic mice had reduced suppressive function compared to Treg from non-ischaemic mice. Fingolimod treatment rescued this function against saline-treated but not fingolimod-treated CD4⁺ effector T cells. In conclusion, fingolimod seems to improve the suppressive function of Treg post-stroke while also increasing the resistance of CD4⁺ effector cells to this suppression. Fingolimod's capacity to increase both effector and regulatory functions may explain the lack of consistent improvement in functional recovery in experimental brain ischaemia.