Quantification and Profiling of Early and Late Differentiation Stage T Cells in Mantle Cell Lymphoma Reveals Immunotherapeutic Targets in Subsets of Patients.

With the aim to advance the understanding of immune regulation in MCL and to identify targetable T-cell subsets, we set out to combine image analysis and spatial omic technology focused on both early and late differentiation stages of T cells. MCL patient tissue (n = 102) was explored using image analysis and GeoMx spatial omics profiling of 69 proteins and 1812 mRNAs. Tumor cells, T helper (TH) cells and cytotoxic (TC) cells of early (CD57-) and late (CD57+) differentiation stage were analyzed. An image analysis workflow was developed based on fine-tuned Cellpose models for cell segmentation and classification. TC and CD57+ subsets of T cells were enriched in tumor-rich compared to tumor-sparse regions. Tumor-sparse regions had a higher expression of several key immune suppressive proteins, tentatively controlling T-cell expansion in regions close to the tumor. We revealed that T cells in late differentiation stages (CD57+) are enriched among MCL infiltrating T cells and are predictive of an increased expression of immune suppressive markers. CD47, IDO1 and CTLA-4 were identified as potential targets for patients with T-cell-rich MCL TIME, while GITR might be a feasible target for MCL patients with sparse T-cell infiltration. In subgroups of patients with a high degree of CD57+ TC-cell infiltration, several immune checkpoint inhibitors, including TIGIT, PD-L1 and LAG3 were increased, emphasizing the immune-suppressive features of this highly differentiated T-cell subset not previously described in MCL.

CD28-CD57+ T cells from head and neck cancer patients produce high levels of cytotoxic granules and type II interferon but are not senescent.

T lymphocytes expressing CD57 and lacking costimulatory receptors CD27/CD28 have been reported to accumulate with aging, chronic infection, and cancer. These cells are described as senescent, with inability to proliferate but enhanced cytolytic and cytokine-producing capacity. However, robust functional studies on these cells taken directly from cancer patients are lacking. We isolated these T cells and their CD27/28+ counterparts from blood and tumor samples of 50 patients with previously untreated head and neck cancer. Functional studies confirmed that these cells have enhanced ability to degranulate and produce IFN-γ. They also retain the ability to proliferate, thus are not senescent. These data suggest that CD27/28-CD57+ CD8+ T cells are a subset of highly differentiated, CD45RA+ effector memory (TEMRA) cells with retained proliferative capacity. Patients with > 34% of these cells among CD8+ T cells in the blood had a higher rate of locoregional disease relapse, suggesting these cells may have prognostic significance.

Multifactorial determinants of NK cell repertoire organization: insights into age, sex, KIR genotype, HLA typing, and CMV influence.

Introduction: Polymorphisms in the KIR and HLA genes contribute to the diversity of the NK cell repertoire. Extrinsic factors also play a role in modifying this repertoire. The best example is cytomegalovirus, which promotes the expansion of memory-like NK cells. However, the mechanisms governing this phenotypic structure are poorly understood. Furthermore, the influence of age and sex has been understudied. Methods: In this study, we examined these parameters in a cohort of 200 healthy volunteer blood donors, focusing on the major inhibitory KIR receptors and CD94/NKG2A, as well as the differentiation marker CD57 and the memory-like population marker NKG2C. Flow cytometry and two joint analyses, unsupervised and semi-supervised, helped define the impact of various intrinsic and extrinsic markers on the phenotypic structure of the NK cell repertoire. Results: In the KIR NK cell compartment, the KIR3DL1 gene is crucial, as unexpressed alleles lead to a repertoire dominated by KIR2D interacting only with HLA-C ligands, whereas an expressed KIR3DL1 gene allows for a greater diversity of NK cell subpopulations interacting with all HLA class I ligands. KIR2DL2 subsequently favors the KIR2D NK cell repertoire specific to C1/C2 ligands, whereas its absence promotes the expression of KIR2DL1 specific to the C2 ligand. The C2C2Bw4+ environment, marked by strong -21T motifs, favors the expansion of the NK cell population expressing only CD57, whereas the absence of HLA-A3/A11 ligands favors the population expressing only NKG2A, a population highly represented within the repertoire. The AA KIR genotype favors NK cell populations without KIR and NKG2A receptors, whereas the KIR B+ genotypes favor populations expressing KIR and NKG2A. Interestingly, we showed that women have a repertoire enriched in CD57- NK cell populations, while men have more CD57+ NK cell subpopulations. Discussion: Overall, our data demonstrate that the phenotypic structure of the NK cell repertoire follows well-defined genetic rules and that immunological history, sex, and age contribute to shaping this NK cell diversity. These elements can contribute to the better selection of hematopoietic stem cell donors and the definition of allogeneic NK cells for cell engineering in NK cell-based immunotherapy approaches.cters are displayed correctly.

CD4+CD57+ senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL-2 inhibitor.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune-mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B-lymphoma-2 (BCL-2) family and interferon-induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL-15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL-2 family and ISGs. Further, treatment with ABT-263 (a senolytic BCL-2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L-PD-1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T-bet+ age-related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL-2 inhibitor ABT-263 may be the potential treatment in ameliorating lupus phenotypes.

CXCL12-CXCR4 mediates CD57+ CD8+ T cell responses in the progression of type 1 diabetes.

CD57+ CD8+ T cells, also referred as effector memory cells, are implicated in various conditions including tumor immunity, virus immunity, and most recently with autoimmunity. However, their roles in the progression and remission of T1D are still unclear. Here, we noted an increase in peripheral CD57+ CD8+ T cells in a T1D patient harboring an activator of transcription 3 (STAT3) mutation. Our in-depth study on the role of CD57+ CD8+ T cells within a T1D patient cohort revealed that these cells undergo significant compositional shifts during the disease's progression. Longitudinal cohort data suggested that CD57+ CD8+ T cell prevalence may be a harbinger of ß-cell function decline in T1D patients. Characterized by robust cytotoxic activity, heightened production of pro-inflammatory cytokines, and increased intracellular glucose uptake, these cells may be key players in the pathophysiology of T1D. Moreover, in vitro assays showed that the CXCL12-CXCR4 axis promotes the expansion and function of CD57+ CD8+ T cells via Erk1/2 signaling. Notably, the changes of serum CXCL12 concentrations were also found in individuals during the peri-remission phase of T1D. Furthermore, treatment with the CXCR4 antagonist LY2510924 reduced the immunological infiltration of CD57+ CD8+ T cells and mitigated hyperglycemia in a STZ-induced T1D mouse model. Taken together, our work has uncovered a novel role of the CXCL12-CXCR4 axis in driving CD57+ CD8+ T cells responses in T1D, and presented a promising therapeutic strategy for delaying the onset and progression of diabetes.

Scrutinizing Clinical Biomarkers in a Large Cohort of Patients with Lyme Disease and Other Tick-Borne Infections.

Standard clinical markers can improve tick-borne infection (TBI) diagnoses. We investigated immune and other clinical biomarkers in 110 patients clinically diagnosed with TBIs before (T0) and after antibiotic treatment (T2). At T0, both the initial observation group and patients without seroconversion for tick-borne pathogens exhibited notably low percentages and counts of CD3 percentage (CD3%), CD3+ cells, CD8+ suppressors, CD4 percentage (CD4%), and CD4+ helper cells, with the latter group showing reductions in CD3%, CD3+, and CD8+ counts in approximately 15-22% of cases. Following treatment at the T2 follow-up, patients typically experienced enhancements in their previously low CD3%, CD3+ counts, CD4%, and CD4+ counts; however, there was no notable progress in their low CD8+ counts, and a higher number of patients presented with insufficient transferrin levels. Moreover, among those with negative serology for tick-borne infections, there was an improvement in low CD3% and CD3+ counts, which was more pronounced in patients with deficient transferrin amounts. Among those with CD57+ (n = 37) and CD19+ (n = 101) lymphocyte analysis, 59.46% of patients had a low CD57+ count, 14.85% had a low CD19 count, and 36.63% had a low CD19 percentage (CD19%). Similar findings were observed concerning low CD57+, CD19+, and CD19% markers for negative TBI serology patients. Overall, this study demonstrates that routine standard clinical markers could assist in a TBI diagnosis.

Obtaining Gene-Modified HLA-E-Expressing Feeder Cells for Stimulation of Natural Killer Cells.

Human cytomegalovirus (HCMV)-specific adaptive NK cells are capable of recognizing viral peptides presented by HLA-E on infected cells via the NKG2C receptor. Using retroviral transduction, we have generated a K562-cell-based line expressing HLA-E in the presence of the HLA-E-stabilizing peptide, which has previously shown the capacity to enhance adaptive NK cell response. The obtained K562-21E cell line was employed to investigate proliferative responses of the CD57- NK cell subset of HCMV-seropositive and seronegative donors. Stimulation of CD57- NK cells with K562-21E/peptide resulted in an increased cell expansion during the 12-day culturing period, regardless of the serological HCMV status of the donor. The enhanced proliferation in response to the peptide was associated with a greater proportion of CD56brightHLA-DR+ NK cells. In later stages of cultivation, the greatest proliferative response to K562-21E/peptide was shown for a highly HCMV-seropositive donor. These expanded NK cells were characterized by the accumulation of CD57-KIR2DL2/3+NKG2C+NKG2A- cells, which are hypothesized to represent adaptive NK cell progenitors. The K562-21E feeder cells can be applied both for the accumulation of NK cells as therapeutic effectors, and for the study of NK cell maturation into the adaptive state after the HLA-E peptide presentation.

Prognostic implications of CD-57 expression in oral squamous cell carcinoma cases.

Natural killer (NK) cells are one of the most important effector T -lymphocytes having antitumor effect. Only a few studies are present in the literature, correlating the expression of cluster of differentiation 57 (CD-57) in NK cells in oral squamous cell carcinoma (OSCC). To analyze the effect of the presence of NK cells in the stroma of OSCC and their effect on the tumor progression and prognosis. A retrospective study was performed over 122 OSCC patients who had undergone surgical treatment between 2014 and 16. Wax blocks were obtained and subjected to immunohistochemical (IHC) analysis for CD-57 expression. Patients were followed up for 3 years and 100 cases were finally included in the study and divided into three groups. The association between variable were studied through the Chi-square test, Kruskal-Wallis test, and Mann-Whitney U test. A total of 91% of cases showed positive staining for CD-57. Maximum positive expression (96.6%) was observed in the patients who were alive and without recurrence (Group-II) as compared to dead patients (Group-I) and in well-differentiated squamous cell carcinoma (WDSCC) cases (96.8%) than in poorly differentiated cases. Also, the mean CD-57 positive cells count was found to be highest in Group-II and WDSCC cases. A significant correlation was observed between CD-57 expression and patients' health status. As the expression of CD-57 increased in the tumor stroma of OSCC, the chances for the patient to be alive were increased; therefore, it may serve as a good prognostic marker.

Comparative Analysis of Cluster of Differentiation 57 and Proliferating Cell Nuclear Antigen Expression in Different Grades of Oral Squamous Cell Carcinoma: An Immunohistochemical Study.

BACKGROUND:  The immune defense against tumor cells is mainly mediated by the natural killer (NK) cells. Cluster of differentiation 57 (CD57) is a 110-kd glycoprotein, typically expressed by the NK cells, attacks the cancer cells and inhibits tumor development. Proliferating cell nuclear antigen (PCNA) is a 36-kd auxiliary protein for DNA polymerase delta that correlates with cell proliferation and DNA synthesis. It is an essential component of DNA replication, DNA recombination, and DNA repair. The uncoordinated proliferation of PCNA protein characterizes the biological behavior of malignant lesions. AIM:  The aim of the present study is to compare and correlate the expression of CD57 and PCNA in different grades of oral squamous cell carcinoma (OSCC) by immunohistochemistry. MATERIALS AND METHODS:  This retrospective analysis comprises 30 samples of various grades of OSCCs and 10 samples of healthy mucosa. Sections of 4-5 µm thickness were done and stained with monoclonal anti-PCNA and anti-CD57 antibodies. The statistical package for social science (SPSS) version 16.0 software (IBM Corp., Armonk, NY) was used to analyze the data in this study. The expression of CD57 and PCNA was compared and correlated between the groups using analysis of variance (ANOVA) post hoc, Dunnet t-test, and Pearson's correlation coefficient test. For statistical significance, a p-value of 0.05 or less was used. RESULTS: A significant decrease in CD57 labeling index was seen from well-differentiated squamous cell carcinoma (16.63 ± 2.33) to poorly differentiated squamous cell carcinoma (5.53 ± 1.20) whereas the significant increase in PCNA labeling index was noted from well-differentiated squamous cell carcinoma (45.88 ± 2.20), followed by moderately differentiated and poorly differentiated squamous cell carcinoma (72.77 ± 4.35). CONCLUSION:  The combination of CD57 and PCNA biomarkers appears to be good indicators of the immune status of the patient and the aggressiveness of the lesion.

Senescent CD153+ T Lymphocytes Increase in the Peripheral Blood of Patients with Thromboangiitis Obliterans.

Background: Buerger's disease, also known as Thromboangiitis Obliterans (TAO), is a progressive, inflammatory vascular disease with unknown etiology. Objective: To address the degree of T cell immunosenescence in this inflammatory disease, the frequency of senescent T cells expressing CD57 and/or CD153 (CD30L) in patients with TAO. Methods: In this study, nine male cigarette smoker patients with TAO, nine male healthy cigarette smokers, and nine male healthy non-smoker blood donors were enrolled. PBMCs were extracted from the blood of all participants and stored in liquid nitrogen before use. The percentages of senescent T cells were detected by flow cytometry. The results were analyzed using non-parametric statistical tests. Results: The frequencies of senescent CD3+CD4+CD57+CD153+ and CD3+CD4+CD57-CD153+ T cells significantly increased in patients compared with the non-smoker controls (p=0.01 and p=0.04, respectively). The frequency of senescent CD3+CD4-CD57-CD153+ T cells was higher in patients compared with the smoker controls (p=0.02). In patients with TAO, CD57+CD153- cells were more frequent in CD3hiCD4- and CD3hiCD4+ T cells compared with the CD3loCD4- and CD3loCD4+ T cells (p=0.008 and p=0.0002, respectively). Conversely, the frequency of CD57-CD153+ T cells was significantly higher in CD3loCD4- T cells compared with the CD3hiCD4- T cells (p=0.004). The percentage of CD3+CD4+CD57+CD153- T cells correlated negatively with smoking level in smoker controls (p=0.02, Spearman r=-0.80). Conclusion: Elevated frequencies of senescent CD4+CD57+CD153+ and CD4+CD57-CD153+ T cells in patients compared with non-smoker and smoker controls suggest the contribution of immunosenescence in TAO.

Emerging insights of NK cells immunosurveillance in histomorphologic prognostic indicators of oral squamous cell carcinoma.

Background: IFN-gamma and natural killer (NK) cells have been considered the most effective cells in the combat of cancer, contributing to better prognosis and longer survival. The aim of the study was to analyze and correlate the CD 57 immunopositive NK cell-mediated Interferon-γ pathway in regulating immune mechanisms in Oral Squamous Cell Carcinoma. Materials and Methodology: The study sample was composed of a total of 40 cases of histopathologically confirmed cases of Oral Squamous cell carcinoma (OSCC). Clinical data such as age, gender, habit history, signs and symptoms, and TNM staging were obtained for each case. The biopsy specimens of the cases obtained were fixed with 10% neutral buffered formalin and processed and embedded in paraffin wax. 3-4 µ thick sections were taken for hematoxylin and eosin staining and immunohistochemistry procedure. A saliva sample was collected from each patient and stored at 20 degree Celsius for estimation of salivary interferon-gamma levels using the sandwich ELISA technique. Results: CD 57 NK cells quantitative assessment was significantly associated with tumor budding, cell nest size, the pattern of invasion, lymphocytic host response, NK cell morphology, Depth of invasion, and Tumor thickness. The ratio of CD 57 immunopositive NK cells to salivary IFN-γ levels showed a significant association with histopathological grades, tumor size, and lymph node status. Conclusion: Adoptive cellular transfer therapy with NK cells has been advocated in both experimental models and clinical trials in treating hematopoietic malignancies. The strategy is based on reviving the patient innate immune surveillance and control of tumor invasion by the infusion of activated NK cells. The IFN-gamma and NK cell infiltration in oral squamous cell carcinoma might show a distinctive tumor microenvironment with a favorable local cytotoxic immune response against neoplastic cells.

CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4+ T cells.

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency (PAD), analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects. CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation. Indeed, while circulating CD57+ CD4+ T cells are normally rare, we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade. We performed single-cell RNA-seq analysis of matched CD57+ CD4+ T cells from blood and tonsil samples. Circulating CD57+ CD4+ T cells (CD4cyt) exhibited a cytotoxic transcriptome similar to that of CD8+ effector cells, could kill B cells, and inhibited B-cell responses. CTLA4 restrained the formation of CD4cyt. While CD57 also marked an abundant subset of follicular helper T cells, which is consistent with their antigen-driven differentiation, this subset had a pre-exhaustion transcriptomic signature marked by TCF7, TOX, and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition. Thus, CD57+ CD4+ T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers. CTLA4 is a key modifier of CD4+ T-cell cytotoxicity, and the pathological CD4cyt phenotype is accentuated by infection.

Dynamics of circulating lymphocytes responding to human experimental enterotoxigenic Escherichia coli infection.

Enterotoxigenic Escherichia coli (ETEC) is an important cause of children's and travelers' diarrhea, with no licensed vaccine. This study aimed to explore the role of cellular immunity in protection against human ETEC infection. Nine volunteers were experimentally infected with ETEC, of which six developed diarrhea. Lymphocytes were collected from peripheral blood buffy coats, before and 3, 5, 6, 7, 10, and 28 days after dose ingestion, and 34 phenotypic and functional markers were examined by mass cytometry. Thirty-three cell populations, derived by manually merging 139 cell clusters from the X-shift unsupervised clustering algorithm, were analyzed. Initially, the diarrhea group responded with increased CD56dim CD16+ natural killer cells, dendritic cells tended to rise, and mucosal-associated invariant T cells decreased. On day 5-7, an increase in plasmablasts was paralleled by a consistent rise in CD4+ Th17-like effector memory and regulatory cell subsets. CD4+ Th17-like central memory cells peaked on day 10. All Th17-like cell populations showed increased expression of activation, gut-homing, and proliferation markers. Interestingly, in the nondiarrhea group, these same CD4+ Th17-like cell populations expanded earlier, normalizing around day 7. Earlier development of these CD4+ Th17-like cell populations in the nondiarrhea group may suggest a recall response and a potential role in controlling ETEC infections.

Erratum: Human pegivirus-1 replication influences NK cell reconstitution after allogeneic haematopoietic stem cell transplantation.

[This corrects the article DOI: 10.3389/fimmu.2022.1060886.].

Development of a human herpesvirus 8-negative effusion-based lymphoma during treatment with dasatinib for chronic myeloid leukemia.

We present the case of an 85-year-old male patient diagnosed with human herpesvirus 8 (HHV8)-negative effusion-based lymphoma (EBL) that developed from long-lasting pleural effusion (PE) induced by dasatinib treatment for chronic myeloid leukemia (CML). After the onset of this disorder, dasatinib treatment was discontinued and drainage was performed to regress the effusion. The major molecular response (MMR) was thus lost. The patient did not tolerate nilotinib treatment, but bosutinib was successful in restoring MMR. During these clinical courses, the patient suffered from a recurrence of EBL, which was treated with rituximab-based chemotherapy. The PE sample just before the 3rd cycle of chemotherapy revealed the proliferation of CD57-positive T cells, along with the disappearance of lymphoma cells. Anti-tumor immunity may have been activated following the immunochemotherapy in the undisturbed immunological environment when both EBL and CML almost regressed. After four cycles of R-CVP therapy, the patient has been in remission for 16 months and no longer requires drainage.

Cord blood derived NK cells activated in counter with tumor cells.

NK cells are initially known for their ability to kill tumor cells with no prior sensitization. Production of mature and long lasting NK cells from Umbilical Cord Blood (UCB) by using cytokines could be a promising method for immunotherapy. NK cells were generated from cord blood cells using IL2, IL7, and IL15 cytokines and measured expression of CD57 and NKp46 markers. Afterward, their capacity in the elimination of malignant cells (Reh cell line) was evaluated by assessment of interferon-γ (as cytokine production sign) and CD107-a expression (as cytotoxic function symptom) using flow cytometry. Our results showed efficient NKp46 + , and CD57 + NK cells generated on day 14. Also, expression of CD107-a and IFN-γ following co-culture with Reh cell lines significantly increased in comparison to the control. Taken together, we have reported one of the best culture conditions for the generation of CD57 + NK cells with on feeder cells and showed appropriate capacity in counter reh cell lines as a target.

Decreased frequency of a novel T-lymphocyte subset, CD3+ CD4- CD7+ CD57- T cells, in hepatitis B virus-related end-stage liver disease might contribute to disease progression.

CD7 and CD57 are related to the differentiation and functional stages of CD8+ T cells. However, the role of their combined presence in CD8+ T cells in patients with chronic hepatitis B virus (HBV) infection, especially those with end-stage liver disease, remains unclear. Blood samples from healthy volunteers and patients with chronic hepatitis B were analyzed via Luminex assay and ELISA to measure plasma cytokine levels. Further, recombinant IL-22 was used to stimulate peripheral blood mononuclear cells from healthy volunteers, and the frequency of CD3+ CD4- CD7+ CD57- T cells and apoptosis rates were investigated via flow cytometry. Patients with end-stage liver disease, particularly those with acute to chronic liver failure, showed decreased CD3+ CD4- CD7+ CD57- T cell frequency. Furthermore, the prevalence of CD3+ CD4- CD7+ CD57- T cells was negatively correlated with disease severity, prognosis, and complications (ascites). We also observed that IL-22 promoted apoptosis and brought about a decrease in the number of CD3+ CD4- CD7+ CD57- T cells in a dose-dependent manner. CD3+ CD4- CD7+ CD57- T cells displayed a B and T lymphocyte attenuator (BTLA)high CD25high CD127high immunosuppressive phenotype and showed low interferon-γ, tumor necrosis factor-α, granzyme A, and perforin expression levels. The present findings will elucidate the pathogenesis of HBV-related end-stage liver disease and aid the identification of novel drug targets.

Decreased CD57 expression of natural killer cells enhanced cytotoxicity in patients with primary sclerosing cholangitis.

Background/aims: Primary sclerosing cholangitis (PSC) is a chronic inflammatory biliary disease for which the immunopathological basis remains an enigma. Natural killer (NK) cells are key components of innate immunity and seemingly play diversified roles in different autoimmune disorders (AIDs). The aim of this study was to determine the role of NK cells in the pathogenesis of PSC. Methods: The frequency and phenotype of circulating NK cells in a large cohort of patients with PSC and healthy controls (HCs) were systematically examined. In addition, the functional capacity of NK cells including cytotoxicity and cytokine production was studied. Results: The frequency of CD3-CD56dimCD16+ (defined as CD56dim) NK cells in PSC patients was significantly lower in comparison to HCs. CD56dim NK cells from PSC displayed a more immature phenotype including high expression of the natural killing receptor NKp46 and downregulation of the highly differentiated NK cell marker CD57. Interestingly, the reduction of CD57 expression of NK cells was associated with the disease severity of PSC. In addition, PSC CD56dim NK cells exhibited increased CD107a degranulation and cytolytic activity toward target cells compared with HCs. Further analysis demonstrated that CD57-CD56dim NK cells from PSC had elevated expression of NKp46, NKp30, IL-2 receptor, and KLRG1 and higher cytotoxic capacity as compared to CD57+CD56dim NK cells. Conclusions: Our data demonstrate that the differentiation of PSC NK cells is dysregulated with enhanced cytotoxic activity. This change is likely to be functionally involved in pathogenesis and disease progression, deducing the potential of NK-directed immunotherapy for PSC.

The molecular mechanism of Ang II induced-AAA models based on proteomics analysis in ApoE-/- and CD57BL/6J mice.

Apolipoprotein knockout (ApoE-/-) and CD57BL/6J mouse models of angiotensin II (Ang II)-induced abdominal aortic aneurysm (AAA) are commonly used in AAA research. However, the similarities and differences in the molecular mechanisms of AAA in these two genotypes have not been reported. In our study, we analyzed proteomics data from ApoE-/- and CD57BL/6J mouse models of Ang II-induced AAA and control mice by LC-MS/MS. Gene set enrichment analysis (GSEA) of differentially abundance proteins (DAPs) in the ApoE-/- or CD57BL/6J mouse groups was performed in R software, and infiltration of immune cells in groups was assessed. DAP that showed the same trend in abundance in ApoE-/- and CD57BL/6J mice (S-DAP) were identified and subjected to GO enrichment, KEGG pathway, and connectivity map (CMap) analyses. The protein-protein interaction (PPI) network of the S-DAP was drawn, the key S-DAP were identified by MCODE, and the transcription factors (TFs) of crucial S-DAP were predicted by iRegulon in Cytoscape. Male ApoE-/- and CD57BL/6J mouse models of Ang II-induced AAA are commonly used in AAA research, and extracellular matrix organization is associated with AAA in both of these models. However, there are some differences between the mechanisms underlying AAA in these two genotypes, and these differences need to be considered when studying AAA and selecting models. SIGNIFICANCE: Our research provided the first insight into the similarity and differential mechanisms of Ang II infused AAA models using ApoE-/- and CD57BL/6J mice. This study might provide the some advises for the selection of Ang II infused AAA models for further AAA researches.