NKT Cells In Patients Research Articles

Cross-Talk between Mucosal-Associated Invariant T, Natural Killer, and Natural Killer T Cell Populations is Implicated in the Pathogenesis of Placenta Accreta Spectrum

The study included 32 women with PAS and 20 with normally implanted placenta as a control group. Vascular endothelial cell growth factor (VEGF), Soluble FMS Like Tyrosine Kinase (sFLT-1/sVEGFR1), and Endoglin (ENG) were measured in placenta tissue by ELISA. Granzyme B (GrzB) expression in trophoblastic and stromal mesenchymal cells was evaluated by immunohistochemistry. MAIT, NK, and NKT cells were assessed in blood and placenta by flow cytometry. Alterations were observed in levels of MAIT cells, NK cell subsets, and NKT cells in patients compared with controls. Several significant correlations were detected between these cells and GrzB scores, VEGF, ENG, and sFLT-1 levels. This is the first study analysing these cells in PAS patients and correlating their levels with changes in some angiogenic and antiangiogenic factors implicated in trophoblast invasion and with GrzB distribution in trophoblast and stroma. Interrelation between these cells probably plays an important role in pathogenesis of PAS.

Aberrant HSP90 Expression in Lymphocytes and HSP90 Response to Anti-PD-1 Therapy in Lymphoma Patients.

HSP90 family of molecular chaperones has been shown to be implicated in various stages of tumor growth and development. Recent studies have highlighted the role of extracellular HSP90 in tumor immunology, however, the role that HSP90 plays in the regulation of immune responses and the impact of cancer immunotherapy, including immune checkpoint blockade, on HSP90 is still unclear. Here we assessed the surface and intracellular expression of constitutive cytosolic HSP90β isoform, mitochondrial HSP90 homolog TRAP1 and co-chaperone STIP1/HOP in T, NK, B and NKT cells derived from peripheral blood and bone marrow samples of patients with Hodgkin and B-cell Non-Hodgkin lymphomas. HSP90β and STIP1 were overexpressed in B lymphocytes, while TRAP1 expression was decreased in T, B, NK and NKT cells of lymphoma patients. HSP90 overexpression in B cells was not associated with malignant B cell clones, since no clonotypic B cells were detected by immunoglobulin heavy chain (IgH) gene rearrangements. PD-1 blockade was found to differently affect the intracellular and surface HSP90 in T, B, NK and NKT cells in patients with relapsed or refractory classical Hodgkin lymphoma. Modulating HSP90 was found to affect the NK cell degranulation response and IFNγ production in lymphoma patients. These findings provide the rationale to further explore HSP90 homologs for improving patient response to cancer immunotherapy.

1769P Circulating T cells and response to neoadjuvant chemotherapy in locally advanced breast cancer

Breast cancer (BC) is the most frequent and leading cause of cancer death among women. Immune system plays a importante role in the development and prognosis of BC. T lymphocytes contribute to tumor immunosurvaillance and preclinical and clinical data indicate that the immune system influences the prognosis and response to chemotherapy. However, there are few data considering circulating T cell and its clinical relevance is not fully established in breast cancer. This study aimed to characterize the profile of circulating T, B, NK and NKT cells in patients with locally advanced breast cancer.

Major reduction of NKT cells in patients with severe COVID-19 pneumonia

BackgroundNK cells seem to be mainly involved in COVID-19 pneumonia. Little is known about NKT cells which represent a bridge between innate and adaptive immunity. MethodsWe characterized peripheral blood T, NK and NKT cells in 45 patients with COVID-19 pneumonia (COVID-19 subjects) and 19 healthy donors (HDs). According to the severity of the disease, we stratified COVID-19 subjects into severe and non-severe groups. ResultsCompared to HDs, COVID-19 subjects showed higher percentages of NK CD57+ and CD56dim NK cells and lower percentages of NKT and CD56bright cells. In the severe group we found a significantly lower percentage of NKT cells. In a multiple logistic regression analysis, NKT cell was independently associated with the severity of the disease. ConclusionsThe low percentage of NKT cells in peripheral blood of COVID-19 subjects and the independent association with the severity of the disease suggests a potential role of this subset.

Curcumin mediates attenuation of pro-inflammatory interferon γ and interleukin 17 cytokine responses in psoriatic disease, strengthening its role as a dietary immunosuppressant

Curcumin exhibits anti-inflammatory properties and has been used for centuries in traditional medicine and as dietary supplement. Data from clinical trials has strengthened the notion that curcumin may exert an anti-inflammatory and immunosuppressive role in patients with psoriatic disease, but its mode of action has remained elusive. We hypothesized that curcumin could inhibit interferon (IFN)-γ and interleukin (IL)-17 production in peripheral blood mononuclear cells from patients with psoriasis and psoriatic arthritis (PsA). To this end, we assessed the in vitro effect of curcumin on IFN-γ production by cluster differentiation (CD)4(+), CD8(+) T cells, natural killer (NK) and NKT cells and on IL-17 production by CD4(+) T cells from 34 patients with psoriatic disease (22 with psoriasis and 12 with PsA); 15 normal subjects were included as healthy controls. We also assessed the effect of curcumin on signal transducer and activator of transcription (STAT)3 activation. Curcumin significantly decreased, in a dose dependent manner, IFNγ-production by CD4(+) and CD8(+) T cells, and NK and NKT cells in patients with psoriatic disease and healthy controls. It also decreased IL-17 production by CD4(+) T cells (Th17). At the molecular level, curcumin increased STAT3 serine 727 phosphorylation intensity and p-STAT3(+) CD4(+) T cells in patients with PsA and psoriasis. In conclusion, curcumin in vitro inhibits pro-inflammatory IFN-γ and IL-17 production in psoriatic disease, and this may strengthen its role as a dietary immunosuppressant in patients with this disease.

Circulating NKT cells in patients with gestational diabetes: Preliminary findings

Circulating NKT cells in patients with gestational diabetes: Preliminary findings

Su1210 The Prognostic Value of the Natural Killers (NK-Cells) in Case of Ulcerative Colitis Depending on Its Severity

The goal: to study the quantitative parameters of the effector NKand NKT-cells of ulcerative colitis patients in case of different activity rate of autoimmune process. Materials and methods: From 2011 till 2012 42 ulcerative colitis (UC) patients being under treatment in the Intestines Pathology Department in CSRIG (Central Scientific Research Institute of Gastroenterology) were studied. 32 of them men, 10 women. The age of the patients ranged from 19 to 70 years, average age 41,3±2,3 (M±σ). The diagnosis was verified using data of clinical, laboratory, immunological, histological and instrumental methods of research. Immunophenotyping of NKand NKT-cells by the method of flow cytometry using twoparameter reagents (CD3-FITC/CD16/56-PE and CD3+FITC/CD16/56-PE, «Bekman Coulter») was performed. The sample was analyzed by flow cytometers FACSCalibur («Bekman Dickinson»). The statistic data analysis was performed using the computer program «STATISTICA 6.0», the statistical significance of the values was verified by the Student t-test. Results: The analysis of lymphocyte parameters determining the killer effect without the help of antigen recognizing receptor of natural killers (NK-cells) showed a significant (p<0,001) reduction of relative and absolute quantity of lymphocytes expressing CD3-CD16+56+ to 6,0±1,2% in patients with heavy UC severity comparing to the patients with mild and medium severity (12,3±1,9 and 17,5±2,5% respectively). A statistically significant reduction (up to 4,6±1,4%, p<0,001) of relative quantity of the CD3+CD16+56+NKT-cells was observed during the study of the patients with heavy UC severity comparing to the patients with mild severity (9,4±1,4%); there was no significant difference between medium and heavy UC severity (p=0,834). Insufficient functioning of natural killers (NK-cells) should be taken into account in connection to the problem of colorectal cancer development in patients with long-lasting progressive state of UC. Conclusion: The obtained data show the decrease of relative and absolute abundance of NKand NKT-cells in patients with heavy UC severity, but it should be noted that apart from the quantitative parameters an important role in the

Comparison between interleukine-17 levels by NK-T cells in patients with chronic hepatitis C and healthy individuals

Comparison between interleukine-17 levels by NK-T cells in patients with chronic hepatitis C and healthy individuals

Upregulation of SCC-S2 in immune cells and tumor tissues of papillary thyroid carcinoma

Studies have shown that SCC-S2 can be detected in cancer cells, but its relation with thyroid cancer remains uncertain. In the current study, we investigated SCC-S2 expression in thyroid cancer from the immune cell perspective and tumor tissue perspective. Levels of SCC-S2 in CD4+ T cells, CD8+ T cells, monocytes, natural killer (NK) T cells, tumor tissues, and adjacent noncancerous thyroid tissues were tested by real-time reverse transcription PCR and Western blot. Results revealed that mRNA and protein levels of SCC-S2 were significantly increased in peripheral CD4+ (mRNA, 1.90-fold; protein, 1.55-fold) and CD8+ T cells (mRNA, 2.37-fold; protein, 1.72-fold) but not monocytes and NKT cells in patients than in healthy donors. Further elevated mRNA level but not protein expression was observed in tumor-infiltrating CD4+ T cells, whereas both mRNA level and protein expression were further increased in tumor-infiltrating CD8+ T cells. Also, mRNA and protein levels of SCC-S2 in thyroid tissues were significantly elevated than those in adjacent noncancerous thyroid tissues. Moreover, patients with cervical lymph node metastasis presented clearly higher mRNA and protein expression of SCC-S2 compared to those without cervical lymph node metastasis (p < 0.05). These results suggest that SCC-S2 may play roles in affecting both immune cells and tumor cells in the thyroid and may indicate a novel pathway for understanding the pathogenesis of the disease.

The aberrant expression of stimulatory and inhibitory killer immunoglobulin-like receptors in NK- and NKT-cells contributes to lupus.

Killer cell immunoglobulin-like receptors (KIR) contribute to the pathogenesis of multiple auto-immune diseases via the modulation of NK-, NKT- and T-cells. Thus, we want to know whether the expression pattern of KIR is associated with systemic lupus erythematosus (SLE) susceptibility. Here, real-time quantitative PCR and fluorescence-activated cell sorting (FACS) were used to measure the stimulatory KIR (sKIR) and inhibitory KIR (iKIR) mRAN and protein levels on NK-, NKT- and T-cells in both SLE patients and healthy controls. In SLE patients, CD158a/h (KIR2DL1/S1) was highly expressed while CD158b/i/j (KIR2DL2/L3/S2, iKIR/iKIR/sKIR) was lowly expressed in NK- and NKT-cells in patients. The expression levels of KIR2DL1 and KIR2DL2 (iKIRs) were decreased while the expression levels of KIR2DS1 (sKIR) were increased in NK- and NKT-cells in the patients. We found that SLE patients represent aberrant expression of stimulatory and inhibitory KIRs in NK- and NKT-cells. Consequently, these different expression levels of KIRs may contribute to the abnormal function of these cells, which lead to the risk of SLE.

WS17.5 Increased apoptosis and lack of invariant NKT cells in patients with cystic fibrosis leads to circulating antinuclear antibodies

WS17.5 Increased apoptosis and lack of invariant NKT cells in patients with cystic fibrosis leads to circulating antinuclear antibodies

Perforin‐Mediated Cytotoxicity in non‐ST Elevation Myocardial Infarction

The aim of this investigation was to examine the role of perforin (P)-mediated cytotoxicity in the dynamics of tissue damage in patients with non-ST-segment elevation myocardial infarction (NSTEMI) treated with anti-ischaemic drugs. We enrolled 48 patients with NSTEMI in this study [age, 71.5 years; 61.5/76 (median, 25th/75th percentiles)]. The percentage of total peripheral blood P(+) lymphocytes was elevated owing to the increased frequency of P(+) cells within natural killer (NK) subsets, T and NKT cells in patients on day 1 after NSTEMI when compared with healthy controls. Positive correlations were found between cardiac troponin I plasma concentrations and the frequency of P(+) cells, P(+) T cells, P(+) NK cells and their CD56(+dim) and CD56(+bright) subsets during the first week after the NSTEMI. The expression of P in NK cells was accompanied by P-mediated cytotoxicity against K-562 targets at all days examined, except day 21, when an anti-perforin monoclonal antibody did not completely abolish the killing. The percentage of P(+) T cells, P(+) NKT cells and P(+) NK subsets was the highest on the day 1 after NSTEMI and decreased in the post-infarction period. CD56(+) lymphocytes were found in damaged myocardium, suggesting their tissue recruitment. In conclusion, patients with NSTEMI have a strong and prolonged P-mediated systemic inflammatory reaction, which may sustain autoaggressive reactions towards myocardial tissue during the development of myocardial infarction.

OL-048 Dynamic changes of CTLs, NK cells, and NKT cells in patients with acute hepatitis B infection

OL-048 Dynamic changes of CTLs, NK cells, and NKT cells in patients with acute hepatitis B infection

EBV-Induced Human CD8+ NKT Cells Suppress Tumorigenesis by EBV-Associated Malignancies

The underlying mechanism of the protective and suppressive role of NKT cells in human tumor immunosurveillance remains to be fully elucidated. We show that the frequencies of CD8(+) NKT cells in patients with EBV-associated Hodgkin's lymphoma or nasopharyngeal carcinoma are significantly lower than those in healthy EBV carriers. These CD8(+) NKT cells in tumor patients are also functionally impaired. In human-thymus-severe combined immunodeficient (hu-thym-SCID) chimeras, EBV challenge efficiently promotes the generation of IFN-gamma-biased CD8(+) NKT cells. These cells are strongly cytotoxic, drive syngeneic T cells into a Th1 bias, and enhance T-cell cytotoxicity to EBV-associated tumor cells. Interleukin-4-biased CD4(+) NKT cells are predominately generated in unchallenged chimeras. These cells are noncytotoxic, drive syngeneic T cells into a Th2 bias, and do not affect T-cell cytotoxicity. In humanized xenogeneic tumor-transplanted hu-thym-SCID chimeras, adoptive transfer with EBV-induced CD8(+) NKT cells significantly suppresses tumorigenesis by EBV-associated malignancies. EBV-induced CD8(+) NKT cells are necessary and sufficient to enhance the T-cell immunity to EBV-associated malignancies in the hu-thym-SCID chimeras. CD4(+) NKT cells are synergetic with CD8(+) NKT cells, leading to a more pronounced T-cell antitumor response in the chimeras cotransferred with CD4(+) and CD8(+) NKT cells. Thus, immune reconstitution with EBV-induced CD8(+) NKT cells could be a useful strategy in management of EBV-associated malignancies.

Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

Natural killer T cells (NKT) are an important subset of T lymphocytes. They are unique in their ability to produce both T helper 1 and T helper 2 associated cytokines, thus being capable of steering the immune system into either inflammation or tolerance. Disruption of NKT cell numbers or function results in severe deficits in immune surveillance against pathogens and tumor cells. Growing experimental evidence suggests that hepatosteatosis may reduce resident hepatic as well as peripheral NKT cells. Those models of hepatosteatosis and the change in NKT cell numbers are associated with a disruption of cytokine homeostasis, resulting in a more pronounced release of proinflammatory cytokines which renders the steatotic liver highly susceptible to secondary insults. In this letter to the editor, we focus on recently published data in the World Journal of Gastroenterology by Xu and colleagues demonstrating reduced peripheral NKT cells in patients with non-alcoholic fatty liver disease, compare those findings with ours and others in different animal models of hepatosteatosis, and hypothesize about the potential underlying mechanism.

The characteristics of human NKT cells in lung cancer—CD1d independent cytotoxicity against lung cancer cells by NKT cells and decreased human NKT cell response in lung cancer patients

The activation of human Vα24 +Vβ11 +natural killer T cells (NKT) cells (Vα24 NKT cells) induces effective antitumor responses with secondary immune effects through activation of conventional T cells and natural killer cells. In this study, we attempted to analyze the characteristics of human NKT cells in lung cancer patients. Vα24 NKT cells stimulated with α-GalCer from healthy volunteers exhibited direct cytotoxic activity against two (RERF-LC-OK and PC-3) of seven human lung cancer cell lines studied. Cytotoxicity by Vα24 NKT cells against human lung cancer cells was dependent on the perforin pathway and independent of Fas/FasL pathway. Intracellular adhesion molecule (ICAM)-1 expression on tumor cells was clearly associated with the cytotoxicity of Vα24 NKT cells. On the other hand, the proportion of Vα24 NKT cells in the patients with lung cancer was lower than that in the healthy volunteers. Furthermore, the proliferative response of Vα24 NKT cells to α-GalCer was significantly lower in the peripheral blood mononuclear cells in the patients with lung cancer. Addition of granulocyte colony-stimulating factor moderately restored the low proliferative response of Vα24 NKT cells in the patients with lung cancer, however the percentage by which the response was restored in these patients was still lower than the natural response in healthy volunteers. These results suggest that Vα24 NKT cells may play a pivotal role or the antitumor response in lung cancer.

The number of CD8+ T cells and NKT cells increases in the aqueous humor of patients with Behçet's uveitis

To determine whether there are differences in the immunopathogenesis of different endogenous uveitis syndromes, the phenotypic characteristics of immune cells were analysed among patients with endogenous uveitis. The aetiology of the uveitis included idiopathic recurrent acute anterior uveitis (18 patients), idiopathic intermediate uveitis (13 patients), Behçet's uveitis (17 patients), Vogt-Koyanagi-Harada syndrome (7 patients), and so on. Flow cytometric analysis was performed using immune cells of the aqueous humor and the peripheral blood during the active phase of intraocular inflammation, and monoclonal antibodies to CD3, CD4, CD8, CD14, CD19, CD56, TCR gammadelta, pan TCR alphabeta and Valpha24. CD8+ T cells were predominant in the aqueous humor of the patients with Behçet's uveitis, whereas CD4+ T cells were mainly found in the aqueous humor of patients other than those with Behçet's uveitis. The number of NKT (CD3+CD56+) cells was significantly higher both in the aqueous humor and the peripheral blood of the patients with Behçet's uveitis compared with the other groups (P < 0.05). CD8+CD56+ cells were the predominant subtype of the increased NKT cells in patients with Behçet's uveitis. In addition, intraocular infiltration of CD14+ cells significantly differed among the uveitis patients (P < 0.05). These results suggest that the immunopathogenesis of endogenous uveitis can vary between syndromes, and that CD8+CD56+ NKT cells may play an important role in the immunopathogenesis of Behçet's uveitis.

Circulating Natural Killer T Cells in Patients with Asthma

Recent studies suggest that therapies targeted at depletion or limiting of natural killer (NK) T cells may be a possible strategy for the treatment of asthma. In the present study, we measured the number of circulating Vα24+NKT cells in 32 asthmatic patients and compared these patients with 29 nonatopic healthy controls. We investigated the relationships between NKT cell number and clinical variables such as the number of eosinophils, the circulating level of IgE, and the severity of asthma. In addition, we also investigated the ability of NKT cells to proliferate in response to α‐galactosyl ceramide (α‐GalCer) in vitro. The Vα24+NKT cell counts of asthmatic patients were significantly lower than those of healthy controls. There were no significant differences observed in asthmatic patients among the subgroups in terms of atopic status and severity. There was no significant correlation between the number of NKT cells and clinical variables. The proliferative response to α‐GalCer of the patients and controls was not significantly different, indicating no intrinsic proliferative defect of NKT cells in asthma. These results suggest that the number of circulating NKT cells was already decreased in patients with asthma. Further study, such as the evaluation of lung NKT cells, will be needed to determine the role of NKT cells in patients with asthma.

Preserved IFN-alpha production of circulating Valpha24 NKT cells in primary lung cancer patients.

Human Valpha24 NKT cells bearing an invariant Valpha24JalphaQ antigen receptor, the counterpart of murine Valpha14 NKT cells, are activated by a specific ligand, alpha-GalCer, in a CD1d-dependent manner. Here, we demonstrate decreased numbers of circulating Valpha24 NKT cells in patients with primary lung cancer compared to healthy volunteers. However, Valpha24 NKT cells and DCs from lung cancer patients were functionally normal, even in the presence of tumor. Furthermore, levels of Valpha24 NKT cells in surgically resected lung tissue appeared to be equivalent to those of Valpha14 NKT cells in the mouse lung. Levels of Valpha24 NKT cells in the tumor tissue itself were increased about 2.5 times. Administration of alpha-GalCer-pulsed DCs expanded Valpha14 NKT cells in the lung more than 10 times, and the increased levels were sustained for 1 week. This may explain the previous finding that alpha-GalCer-pulsed DCs exerted strong antitumor activity in mouse lung tumor metastatic models. The potential use of alpha-GalCer-pulsed DCs for immunotherapy aimed at activating endogenous Valpha24 NKT cells in the lung of cancer patients is discussed.