Most knowledge on NK cells is based on studies of what are now known as conventional NK cells in the mouse spleen or human peripheral blood. However, recent studies in mice indicate the presence of ...tissue-resident NK cells in certain organs, such as the liver, that display different markers and transcription factor dependencies as compared with conventional NK cells. In this study, we provide evidence from cytometry by time-of-flight analysis and humanized mice indicating that human CD49e
NK cells are tissue resident in the liver. Thus, these studies indicate that tissue-resident NK cells are evolutionarily conserved in humans and mice, providing a foundation to explore their role in human disease.
Objective
Chikungunya virus (CHIKV) is an arthritogenic mosquito‐transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV‐infected patients develop inflammatory ...arthritis that can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV‐related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.
Methods
Patient history was obtained and physical examination and laboratory tests were performed. All patients with CHIKV‐related arthritis had detectable levels of anti‐CHIKV IgG. Using cytometry by time‐of‐flight (CyTOF), we analyzed peripheral blood mononuclear cells in CHIKV‐infected patients, healthy controls, and patients with untreated, active RA.
Results
Among 10 CHIKV‐infected individuals, 8 developed persistent symmetric polyarthritis that met the American College of Rheumatology/European League Against Rheumatism 2010 criteria for (seronegative) RA. CyTOF analysis revealed that RA and CHIKV‐infected patients had greater percentages of activated and effector CD4+ and CD8+ T cells than healthy controls.
Conclusion
In addition to similar clinical features, patients with CHIKV infection and patients with RA develop very similar peripheral T cell phenotypes. These overlapping clinical and immunologic features highlight a need for rheumatologists to consider CHIKV infection when evaluating patients with new, symmetric polyarthritis.
Nrf2 is a redox-responsive transcription factor that has been implicated in the regulation of DC immune function. Loss of Nrf2 results in increased co-stimulatory molecule expression, enhanced T cell ...stimulatory capacity, and increased reactive oxygen species (ROS) levels in murine immature DCs (iDCs). It is unknown whether altered immune function of Nrf2-deficient DCs (Nrf2−/− iDCs) is due to elevated ROS levels. Furthermore, it is unclear which intracellular signaling pathways are involved in Nrf2-mediated regulation of DC function. Using antioxidant vitamins to reset ROS levels in Nrf2−/− iDCs, we show that elevated ROS is not responsible for the altered phenotype and function of these DCs. Pharmacological inhibitors were used to explore the role of key MAPKs in mediating the altered phenotype and function in Nrf2−/− iDCs. We demonstrate that the increased co-stimulatory molecule expression (MHC II and CD86) and antigen-specific T cell activation capacity observed in Nrf2−/− iDCs was reversed by inhibition of p38 MAPK but not JNK. Importantly, we provide evidence for increased phosphorylation of cAMP-responsive element binding protein (CREB) and activating transcription factor 1 (ATF1), transcription factors that are downstream of p38 MAPK. The increased phosphorylation of CREB/ATF1 in Nrf2−/− iDCs was sensitive to p38 MAPK inhibition. We also show data to implicate heme oxygenase-1 as a potential molecular link between Nrf2 and CREB/ATF1. These results indicate that dysregulation of p38 MAPK-CREB/ATF1 signaling axis underlies the altered function and phenotype in Nrf2-deficient DCs. Our findings provide new insights into the mechanisms by which Nrf2 mediates regulation of DC function.
Background: Nrf2 is required for normal dendritic cell immune functions.
Results: Loss of Nrf2 alters DC function and results in hyperphosphorylation of CREB/ATF1 transcription factors that are responsive to p38 MAPK inhibition.
Conclusion: The p38 MAPK-CREB/ATF1 axis contributes to Nrf2-mediated regulation of DC function.
Significance: Defining the relevance of p38-CREB/ATF1 in Nrf2 signaling expands understanding of DC biology.
Chikungunya virus (CHIKV) is an arthritogenic mosquito-transmitted alphavirus that spread to the Caribbean in 2013 and to the US in 2014. CHIKV-infected patients develop inflammatory arthritis that ...can persist for months or years, but little is known about the rheumatologic and immunologic features of CHIKV-related arthritis in humans, particularly as compared to rheumatoid arthritis (RA). The purpose of this study was to describe these features in a group of 10 American travelers who were nearly simultaneously infected while visiting Haiti in June 2014.
Patient history was obtained and physical examination and laboratory tests were performed. All patients with CHIKV-related arthritis had detectable levels of anti-CHIKV IgG. Using cytometry by time-of-flight (CyTOF), we analyzed peripheral blood mononuclear cells in CHIKV-infected patients, healthy controls, and patients with untreated, active RA.
Among 10 CHIKV-infected individuals, 8 developed persistent symmetric polyarthritis that met the American College of Rheumatology/European League Against Rheumatism 2010 criteria for (seronegative) RA. CyTOF analysis revealed that RA and CHIKV-infected patients had greater percentages of activated and effector CD4+ and CD8+ T cells than healthy controls.
In addition to similar clinical features, patients with CHIKV infection and patients with RA develop very similar peripheral T cell phenotypes. These overlapping clinical and immunologic features highlight a need for rheumatologists to consider CHIKV infection when evaluating patients with new, symmetric polyarthritis.
Malaria parasites that infect birds can have narrow or broad host-tropisms. These differences in host specificity make avian malaria a useful model for studying the evolution and transmission of ...parasite assemblages across geographic ranges. The molecular mechanisms involved in host-specificity and the biology of avian malaria parasites in general are important aspects of malaria pathogenesis that warrant further examination. Here, the transcriptome of the malaria parasite Plasmodium gallinaceum was characterized to investigate the biology and the conservation of genes across various malaria parasite species.
The P. gallinaceum transcriptome was annotated and KEGG pathway mapping was performed. The ripr gene and orthologous genes that play critical roles in the purine salvage pathway were identified and characterized using bioinformatics and phylogenetic methods.
Analysis of the transcriptome sequence database identified essential genes of the purine salvage pathway in P. gallinaceum that shared high sequence similarity to Plasmodium falciparum when compared to other mammalian Plasmodium spp. However, based on the current sequence data, there was a lack of orthologous genes that belonged to the erythrocyte-binding-like (EBL) and reticulocyte-binding-like homologue (RH) family in P. gallinaceum. In addition, an orthologue of the Rh5 interacting protein (ripr) was identified.
These findings suggest that the pathways involved in parasite red blood cell invasion are significantly different in avian Plasmodium parasites, but critical metabolic pathways are conserved throughout divergent Plasmodium taxa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Objectives
To facilitate disease prognosis and improve precise immunotherapy of gastric cancer (GC) patients, a comprehensive study integrating immune cellular and molecular analyses on tumor tissues ...and peripheral blood was performed.
Methods
The association of GC patients’ outcomes and the immune context of their tumors was explored using multiplex immunohistochemistry (mIHC) and transcriptome profiling. Potential immune dysfunction mechanism/s in the tumors on the systemic level was further examined using mass cytometry (CyTOF) in complementary peripheral blood from selected patients. GC cohorts with mIHC and gene expression profiling data were also used as validation cohorts.
Results
Increased CD4+FOXP3+ T‐cell density in the GC tumor correlated with prolonged survival. Interestingly, CD4+FOXP3+ T cells had a close interaction with CD8+ T cells rather than tumor cells. High densities of CD4+FOXP3+ T cells and CD8+ T cells (High‐High) independently predicted prolonged patient survival. Furthermore, the interferon‐gamma (IFN‐γ) gene signature and PDL1 expression were up‐regulated in this group. Importantly, a subgroup of genomically stable (GS) tumors and tumors with chromosomal instability (CIN) within this High‐High group also had excellent survival. The High‐High GS/CIN tumors were coupled with increased frequencies of Tbet+CD4+ T cells and central memory CD4+ T cells in the peripheral blood.
Conclusion
These novel findings identify the combination of CD8+ T cells and FOXP3+CD4+ T cells as a significant prognostic marker for GC patients, which also could potentially be targeted and applied in the combination therapy with immune checkpoint blockades in precision medicine.
In this work, we show an increased CD4+FOXP3+ T cell density in the tumour core correlated with prolonged survival and CD4+FOXP3+ T cells clustered with CD8+ T cells rather than tumour cells. High density of CD4+FOXP3+ T cells and CD8+ T cells (High‐High) independently predicted prolonged patient survival. These High‐High tumours were coupled with an increased IFN‐γ response, antigen presentation, DCs differentiation and PDL1 upregulation in the local tumours, as well as enrichment of Tbet+ CD4+ T cells and central memory CD4+ T cells circulating in the peripheral blood.
Dendritic cells (DCs) are critical mediators of immunity and immune tolerance by orchestrating multiple aspects of T cell activation and function. Immature DCs (iDCs) expressing low levels of ...co-stimulatory receptors are highly efficient at antigen capture but are poor activators of T cells. Maturation of DCs is associated with increased expression of co-stimulatory molecules. Co-stimulatory receptor gene expression is regulated by intracellular redox, NF-κB, and MAPK pathways and by histone deacetylase (HDAC) activity. The transcription factor, Nrf2, is important for maintaining intracellular glutathione (GSH) levels and redox homeostasis and has been implicated in modulating DC co-stimulatory receptor expression. It is unclear whether Nrf2 mediates this effect by GSH-dependent mechanisms and whether it influences DC signaling pathways. Using bone marrow-derived iDCs from Nrf2+/+ and Nrf2−/− mice, we demonstrate that Nrf2−/− iDCs have lower basal GSH levels, enhanced co-stimulatory receptor expression, impaired phagocytic functions, and increased antigen-specific CD8 T cell stimulation capacity. Interestingly, lowering GSH levels in Nrf2+/+ iDCs did not recapitulate the Nrf2−/− iDC phenotype. Loss of Nrf2 resulted in elevated basal levels of reactive oxygen species but did not affect basal NF-κB activity or p38 MAPK phosphorylation. Using pharmacological inhibitors, we demonstrate that enhanced co-stimulatory receptor phenotype of Nrf2−/− iDC does not require ERK activity but is dependent on HDAC activity, indicating a potential interaction between Nrf2 function and HDAC. These results suggest that Nrf2 activity is required to counter rises in intracellular reactive oxygen species and to regulate pathways that control DC co-stimulatory receptor expression.
Nrf2 has been implicated in regulating immune cell signaling and function.
Nrf2-deficient murine DCs exhibit enhanced maturation phenotype, increased ROS levels with dysregulation of antigen uptake capabilities, and altered intracellular signaling.
Nrf2 regulates DC intracellular redox and immune function.
Defining the role of Nrf2 in DC biology underpins development of potential Nrf2 targeted immunotherapeutics.
CD28 superagonist (CD28SA), a therapeutic immunomodulatory monoclonal antibody triggered rapid and exaggerated activation of CD4
+
effector memory T cells (T
EMs
) in humans with unwanted serious ...adverse effects. It is well known that distinct metabolic programs determine the fate and responses of immune cells. In this study, we show that human CD4
+
T
EMs
stimulated with CD28SA adopt a metabolic program similar to those of tumor cells with enhanced glucose utilization, lipid biosynthesis, and proliferation in hypoxic conditions. Identification of metabolic profiles underlying hyperactive T cell activation would provide a platform to test safety of immunostimulatory antibodies.
Tumor-infiltrating lymphocytes (TILs) are an important prognostic indicator in melanoma and play a key role in the patient's response to immune checkpoint blockade. However, until recently, it was ...not possible to combine multi-parameter markers to define the TILs and their histological context. Multiplex immunohistochemistry (mIHC) is a new technology which addresses this issue and enables simultaneous detection of melanoma and multiple immune subsets in formalin fixed paraffin embedded tissue. Following antigen retrieval, melanoma tissue sections are stained by OPAL on an autostainer, including serial rounds of epitope labelling with monoclonal antibodies followed by tyramide signal amplification (TSA). The stained tissue sections are then imaged on the Vectra instrument, and digital images are processed by analysis software (inForm and HALO) to derive tissue segmentation and immune subset densities within the tumor and tumor stroma. Spatial relationships between immune cells and tumor cells are then analyzed using a novel R algorithm. Taken together, multiplex IHC describes the histological context of the immune system in melanoma. The data is objective and allows for characterization of individual melanomas as T cell inflamed (hot), immune excluded, or no immune cells (cold).
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