CD4+CD25?LAG3+ regulatory T cells controlled by the transcription factor Egr-2

Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4⁺CD25⁻Foxp3⁻ T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although ≈2% of the CD4⁺CD25⁻ T cell population consisted of CD4⁺CD25⁻LAG3⁺ T cells in the spleen, CD4⁺CD25⁻LAG3⁺ T cells are enriched to ≈8% in the Peyer''s patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4⁺CD25⁻LAG3⁺ Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naïve CD4⁺ T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4⁺ T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3⁺ natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4⁺CD25⁻LAG3⁺ Tregs. In contrast, the number of CD4⁺CD25⁻LAG3⁺ Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2⁺LAG3⁺CD4⁺ Tregs can be exploited for the control of peripheral immunity.     

Brief Definitive Report: Human visceral leishmaniasis is not associated with expansion or accumulation of Foxp3+ CD4 cells in blood or spleen

Natural regulatory T cells (CD4⁺ CD25⁺ Foxp3⁺), natural regulatory T cells (nTreg), play an important role in the regulation of inflammatory immune responses. However, the immunosuppressive properties of nTreg may unfavourably affect the host’s ability to clear certain infections. In human visceral leishmaniasis (VL), reports on the frequency and function of nTreg are not conclusive. A limitation of our own previous studies that did not indicate a major role for Foxp3⁺ nTreg in VL pathogenesis was that Foxp3 was measured by mRNA expression alone, as other tools were not available at the time. We have in this study assessed CD4⁺CD25⁺Foxp3⁺ cells in splenic aspirates and peripheral blood mononuclear cells (PBMC) from an extensive series of patients with VL and endemic controls (EC) by flow cytometry (FACS). The results do not show increased frequencies of Foxp3⁺ cells in patient with VL pre‐ and post‐treatment, neither were they elevated when compared to PBMC of EC. We conclude that active VL is not associated with increased frequencies of peripheral Foxp3 Treg or accumulation at the site of infection.     

Immunobiology of hepatitis B virus infection

The adaptive immune response, particularly the virus‐specific CD8⁺ T‐cell response, is largely responsible for viral clearance and disease pathogenesis during hepatitis B virus (HBV) infection. The HBV‐specific CD8⁺ T‐cell response is vigorous, polyclonal and multispecific in acutely infected patients who successfully clear the virus and relatively weak and narrowly focused in chronically infected patients. The immunological basis for this dichotomy is unclear. A recent study using HBV transgenic mice and HBV‐specific T‐cell receptor transgenic mice suggests that intrahepatic antigen presentation by HBV positive hepatocytes suppresses HBV‐specific CD8⁺ T‐cell responses through a co‐inhibitory molecule, programmed cell death 1 (PD‐1). In contrast, antigen presentation by activated professional antigen‐presenting cells induces functional differentiation of HBV‐specific CD8⁺ T cells. These findings suggest that the outcome of T‐cell priming is largely dependent on the nature of antigen‐presenting cells. Another study suggests that the timing of HBV‐specific CD4⁺ T‐cell priming regulates the magnitude of the HBV‐specific CD8⁺ T‐cell response. Other factors that could regulate HBV‐specific cellular immune responses are high viral loads, mutational epitope inactivation, T‐cell receptor antagonism and infection of immunologically privileged tissues. However, these pathways become apparent only in the setting of an ineffective cellular immune response, which is therefore the fundamental underlying cause. Understanding the cellular and molecular mechanisms by which HBV evades host immune responses will eventually help develop new immunotherapeutic strategies designed to terminate chronic HBV infection.     

JAK inhibition induces silencing of T Helper cytokine secretion and a profound reduction in T regulatory cells

CD4⁺ T cells maintain cancer surveillance and immune tolerance. Chronic inflammation has been proposed as a driver of clonal evolution in myeloproliferative neoplasms (MPN), suggesting that T cells play an important role in their pathogenesis. Treatment with JAK inhibitors (JAKi) results in improvements in MPN‐associated constitutional symptoms as well as reductions in splenomegaly. However, effects of JAKi on T cells in MPN are not well established and the baseline immune signature remains unclear. We investigated the frequency and function of CD4⁺ T cell subsets in 50 MPN patients at baseline as well as during treatment with either ruxolitinib or fedratinib in a subset. We show that CD4⁺ CD127^low CD25^high FOXP3⁺ T regulatory cells are reduced in MPN patients compared to healthy controls and that this decrease is even more pronounced following JAKi therapy. Moreover, we show that after 6 months of treatment the number of T helper (Th)‐17 cells increased. We also describe a functional ‘silencing’ of T helper cells both in vivo and in vitro and a blockade of pro‐inflammatory cytokines from these cells. This profound effect of JAKi on T cell function may underlay augmented rates of atypical infections that have been reported with use of these drugs.     

Immunoregulatory actions of melatonin and zinc during chronic Trypanosoma cruzi infection

After one century of the discovery of Chagas' disease and the development of an efficient drug with amplitude of actions both in the acute and chronic phase is still a challenge. Alternative immune modulators have been exhaustively used. For that purpose, melatonin and zinc were administered during chronic Trypanosoma cruzi‐infected Wistar rats and several endpoints were assessed. Melatonin has a remarkable functional versatility, being associated with important antioxidant, anti‐inflammatory, and anti‐apoptotic effects. The cross‐talk between zinc and the immune system includes its ability to influence the production and signaling of numerous inflammatory cytokines in a variety of cell types. Our study showed that zinc triggered a decrease in the generation of IFN‐γ for TCD4⁺ cells. Reduced percentage of CD4⁺T cells producing TNF‐α was observed in control melatonin or zinc‐and‐melatonin‐treated animals as compared with untreated rats. On the other hand, a significant increase in the percentage of IL‐4 from CD4⁺ and CD8⁺ T lymphocytes producers was observed 60 days after infection, for all zinc‐treated animals, whether infected or not. Melatonin and zinc therapies increased the percentages of CD4⁺ and CD8⁺ T lymphocytes IL‐10 producers. CD4⁺CD25^highFoxp3⁺ T cells were also elevated in zinc‐ and melatonin‐treated animals. The modulation of the immune system influenced by these molecules affected cytokine production and the inflammatory process during chronic T. cruzi infection. Elucidation of the interplay between cytokine balance and the pathogenesis of Chagas’ disease is extremely relevant not only for the comprehension of the immune mechanisms and clinical forms but, most importantly, also for the implementation of efficient and adequate therapies.     

Activating killer immunoglobulin‐like receptor incompatibilities enhance graft‐versus‐host disease and affect survival after allogeneic hematopoietic stem cell transplantation

Objectives: Killer immunoglobulin‐like receptors (KIRs) regulate function of natural killer (NK) cells and a subset of T cells. In this study, we prospectively evaluated the impact of donor and recipient activating KIR genes on outcome of allogeneic hematopoietic stem cell transplantation (alloHSCT) for patients with hematological malignancies. Methods: One‐hundred consecutive recipients of myeloablative transplantation and their donors were tested for KIR genotype as well as for immune reconstitution, including activating KIR expression on NK cells and T cells. Results: In a multivariate analysis, mismatches of particular activating KIRs such that the patient was negative and the donor was positive (P^?D⁺) resulted in increased risk of acute (KIR2DS1) and chronic (KIR2DS3) graft‐versus‐host disease (GVHD) as well as relapse (KIR2DS5). KIR2DS1 incompatibility in the same direction in the presence of HLA‐C‐group 2 ligand in recipient was associated with reduced overall (risk ratio, RR = 3.01; P = 0.01) and disease‐free survival (RR = 2.92, P = 0.03). Activating mismatches in P^?D⁺ direction resulted in decreased CD4⁺ : CD8⁺ T‐cell ratio up to 1 yr after alloHSCT, as a consequence of decreased CD3⁺CD4⁺ number within the first 100 d and increased CD3⁺CD8⁺ number in later time‐points. Among six evaluated patients, expression of activating KIRs on NK cells and T cells was particularly prominent for those developing intestinal GVHD. Conclusion: Our findings indicate that the presence of particular activating KIRs in donor with their absence in recipient enhances GVHD, which is not accompanied by graft‐versus‐leukemia effect. Evaluation of activating KIR genotype may allow optimization of both donor selection and transplantation procedure in order to avoid GVHD.     

Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss

Viral load reduction facilitates recovery of antiviral T‐cell responses. Dynamic alterations in intrahepatic viraemia clearance and immune cell reactivity during the early phase of nucleoside analogue (NA) therapy and the impact of these changes on HBeAg seroconversion are unknown. Fifteen HBeAg‐positive chronic hepatitis B (CHB) patients were treated with adefovir dipivoxil. T‐cell reactivity to HBV core and surface antigens were tested using ELISPOT assay from baseline to week 48 post‐treatment (at 4‐week intervals). Before and at week 12 of treatment, paired liver biopsies were analysed for intrahepatic HBV‐DNA and cccDNA via real‐time fluorescent PCR. In situ detection of CD4⁺, CD8⁺ T cells and NK cells was analysed by immunohistochemistry. With viral load reduction, HBV‐specific IFN‐γ‐producing CD4⁺ T cells in patients with HBeAg loss were greatly enhanced and reached the highest level at week 12, with further increase observed between week 36 and week 48. After 12 weeks of treatment, total intrahepatic HBV‐DNA and cccDNA had significantly decreased; however, there was no difference in the viral loads or extent of reduction between patients with and without HBeAg loss. Paralleling reduction in viral load, intrahepatic CD8⁺T lymphocytes increased in patients with HBeAg loss compared with baseline values. Only one patient without HBeAg loss exhibited similar results. Increased immune cells were observed in certain patients along with reduced hepatic viral loads during the second phase of HBV‐DNA decline, which could promote the recovery of antiviral immunity and facilitate HBeAg loss.     

Myeloma cells act as tolerogenic antigen‐presenting cells and induce regulatory T cells in vitro

Regulatory T cells (Tregs) are essential for maintenance of self‐tolerance; however, tumor cells can exploit the tolerance to escape the immune system. We investigated the Tregs frequency in patients with multiple myeloma (MM) and in those with monoclonal gammopathy of undetermined significance (MGUS), and found that CD4⁺FoxP3⁺ and CD8⁺FoxP3⁺ Tregs were significantly increased in patients with MM and correlated with the active phase. Both Tregs subsets were expanded in cocultures of CD3⁺ lymphocytes and fresh CD138⁺ MM plasma cells or RPMI8226 and U266 cell lines and functioned as natural (n) and inducible (i) Tregs insofar as they inhibited the proliferation of stimulated CD3 lymphocytes via contact‐dependent and contact‐independent pathways. Induction of Tregs by MM plasma cells required a contact‐dependent pathway, implying antigen recognition by T cells. MM plasma cells acted as immature and tolerogenic antigen‐presenting cells (APCs), in that they displayed low CD80/CD86 expression associated with a phagocytic activity. By acting as immature APCs, MM plasma cells plausibly expand (n)Tregs and (i)Tregs both through conversion of CD3⁺FoxP3^? into CD3⁺FoxP3⁺ T cells and proliferation of CD3⁺FoxP3⁺ T cells, which may suppress the anti‐MM immune response.     

Expansion of circulating CD56bright natural killer cells in patients with JAK2‐positive chronic myeloproliferative neoplasms during treatment with interferon‐α

In recent years, major molecular remissions have been observed in patients with JAK2‐positive chronic myeloproliferative neoplasms (MPNs) after therapy with IFN‐α. IFN‐α is known to have altering effects on immune cells involved in immune surveillance and might consequently enhance anti‐tumor immune response against the JAK2‐mutated clone. The objective of this study was to investigate circulating levels and phenotype of natural killer cells in 29 JAK2‐positive MPN patients during IFN‐α treatment. Furthermore, functional studies of NK cells upon target‐cell recognition and cytokine stimulation were performed. The CD56^bright and CD56^dim NK cell subtypes display different properties in terms of cytokine production and cytotoxicity, respectively. Our results show a significant increase in the proportion of CD56^bright NK cells and a decreasing CD56^dim population during treatment with IFN‐α compared to patients that are untreated, treated with hydroxyurea and healthy controls, P < 0.0001. Furthermore, an overall increase in cytokine‐dependent (IL‐12 and IL‐15) IFN‐γ expression by CD56^dim NK cells during IFN‐α treatment was observed. In contrast, our data indicate a compromised NK cell response to target‐cell recognition during treatment with IFN‐α in four patients. We also report low levels of circulating NK cells in untreated patients compared to healthy donors, patients treated with hydroxyurea and IFN‐α, P = 0.02. Based on our findings, one might speculate whether treatment with IFN‐α skews the human NK population toward a helper type that may assist in CD8⁺ T cell priming in lymphoid tissues at the expense of their immediate cytotoxic functions in peripheral blood and tissues.     

The antiapoptotic activity of Heligmosomoides polygyrus antigen fractions

Our study identified Heligmosomoides polygyrus antigen factors with potential activity for regulation of T‐cell proliferation and surviving of CD4⁺CD25^?, CD4⁺CD25^hi and CD3⁺CD8⁺ cell populations. The antiapoptotic activity of antigenic fractions separated by HPLC was evaluated in vitro after exposure of cells to DEX and rTNF‐α. Different populations of cells responded to antigen fractions in distinct pattern; the most sensitive population of cells to H. polygyrus products were CD4⁺CD25^hi after exposure to DEX and CD3⁺CD8⁺ T cells after exposure to rTNF‐α. H. polygyrus antigens may influence survival of CD8⁺ T cells by regulation of c‐FLIP rather than Bcl‐2, which affects survival of CD4⁺CD25^hi Treg cells and CD4⁺ T cells. Activation of NF‐κB subunits, for example, p50 and p65 was essential for resistance of cells to apoptosis, and antigenic fractions F9 and F17 exerted different effect to F13. The most active fraction in inhibition of apoptosis was F9, which includes Hsp‐60, calumenin, ferritin, galectin and thrombospondin. This study may provide new clues for recognition of factors that regulate the immune response during infection and which engage the TNF‐α receptor‐mediated and the mitochondria‐mediated death pathway.     

Hepatic compartmentalization of exhausted and regulatory cells in HIV/HCV‐coinfected patients

Accelerated intrahepatic hepatitis C virus (HCV) pathogenesis is likely the result of dysregulation within both the innate and adaptive immune compartments, but the exact contribution of peripheral blood and liver lymphocyte subsets remains unclear. Prolonged activation and expansion of immunoregulatory cells have been thought to play a role. We determined immune cell subset frequency in contemporaneous liver and peripheral blood samples from chronic HCV‐infected and HIV/HCV‐coinfected individuals. Peripheral blood mononuclear cells (PBMC) and biopsy‐derived liver‐infiltrating lymphocytes from 26 HIV/HCV‐coinfected, 10 chronic HCV‐infected and 10 HIV‐infected individuals were assessed for various subsets of T and B lymphocytes, dendritic cell, natural killer (NK) cell and NK T‐cell frequency by flow cytometry. CD8⁺ T cells expressing the exhaustion marker PD‐1 were increased in HCV‐infected individuals compared with uninfected individuals (P = 0.02), and HIV coinfection enhanced this effect (P = 0.005). In the liver, regulatory CD4⁺CD25⁺Foxp3⁺ T cells, as well as CD4⁺CD25⁺PD1⁺ T cells, were more frequent in HIV/HCV‐coinfected than in HCV‐monoinfected samples (P < 0.001). HCV was associated with increased regulatory T cells, PD‐1⁺ T cells and decreased memory B cells, regardless of HIV infection (P ≤ 0.005 for all). Low CD8⁺ expression was observed only in PD‐1⁺CD8⁺ T cells from HCV‐infected individuals and healthy controls (P = 0.002) and was associated with enhanced expansion of exhausted CD8⁺ T cells when exposed in vitro to PHA or CMV peptides. In conclusion, in HIV/HCV coinfection, ongoing HCV replication is associated with increased regulatory and exhausted T cells in the periphery and liver that may impact control of HCV. Simultaneous characterization of liver and peripheral blood highlights the disproportionate intrahepatic compartmentalization of immunoregulatory T cells, which may contribute to establishment of chronicity and hepatic fibrogenesis in HIV coinfection.     

Antigenic fractions of Leishmania (Viannia) braziliensis: the immune response characterization of patients at the initial phase of disease

American cutaneous leishmaniasis (ACL) has different clinical manifestations and these manifestations are dependent on the immunological status of the host. As CD4⁺ and CD8⁺ T cells and their mediators play a fundamental role in the host response to Leishmania and there is also a search for antigenic molecules to be used as future vaccines and tools for prognostic tests, this study characterized ACL patients’ immune response after stimulation with soluble and insoluble fractions of L. (V.) braziliensis. We demonstrated a prevailing production of the Th2 cytokines, IL‐4 and IL‐10 and a specific production of IFN‐γ and TNF‐α in patients before treatment. There was also a predominance of CD4⁺ T cells and a small percentage CD8⁺ T cells. The insoluble antigenic fraction primarily stimulated CD4⁺ T cells, while the soluble antigenic fraction showed a mixed profile, with CD4⁺ T cells being the main responsible for Th2 cytokines and CD8⁺ T cells for Th1 cytokines. Therefore, our results showed that a down‐modulation of the Th1 type of response occurs in the initial phase of L. braziliensis disease, being the antigenic fractions capable of stimulating a specific immune response.     

Ethanol consumption modifies dendritic cell antigen presentation in mice

Background:  Alcohol consumption impairs type 1 cell‐mediated adaptive immune responses both in vivo and in vitro. The present study investigated the effect of alcohol consumption on antigen‐presenting cell (APC) populations and cytokine production. Methods:  BALB/c were fed ethanol‐containing, pair‐fed isocaloric liquid control, or solid diets for 11 days. Macrophage and dendritic cell (DC) populations were isolated by paramagenetic bead separation and used to present ovalbumin (OVA) to highly purified syngeneic CD4⁺ T cells derived from DO11.10 T cell receptor transgenic mice in coculture. DC isolated from diet‐fed mice were also used to present OVA to highly purified CD4⁺ T cells derived from antigen‐naïve DO11.10Rag2^?/? mice that are devoid of memory T cells. In vitro cytokine responses, interleukin (IL) ‐2, IL‐6, IL‐12, IL‐13, IL‐17A, and interferon‐γ (IFN‐γ) were measured by enzyme‐linked immunosorbent assay. Flow cytometry measured cell surface molecule expression. Results:  Alcohol consumption impairs delayed hypersensitivity responses (type 1) and enhances serum IgE levels (type 2). CD11c⁺ DC, but not F4/80⁺ macrophages, support cytokine responses by purified CD4⁺ T cells. CD11c⁺ DC derived from ethanol consuming BALB/c mice show diminished ability to support IFN‐γ responses by purified CD4⁺ T cells derived from DO11.10 or DO11.10Rag2^?/? mice. Subset analysis indicates that of the 3 “conventional” DC subsets found in mouse spleens, CD11c⁺CD8⁺ DCs are both responsible for OVA presentation and susceptible to the effects of ethanol. Ethanol consumption does not overtly alter the percent of splenic DC, but does increase the surface density of CD11c on these cells. Data show that cocultures containing purified CD4⁺ T DO11.10 cells and APC derived from alcohol‐consuming mice show decreased IL‐6, IL‐12, IL‐17A, and IFN‐γ and increased IL‐13 cytokine production in response to OVA stimulation. Conclusions:  Ethanol alters CD11c⁺CD8⁺ DC function, affecting cytokines responsible for adaptive immune responses. A unifying hypothesis for the underlying mechanism(s) of ethanol’s effect upon adaptive immune function is proposed.     

Age-matched lymphocyte subpopulation reference values in childhood and adolescence: application of exponential regression analysis

Background: Normal values of lymphocyte subpopulations for healthy children and adults have been published in defined age groups exclusively, which results in difficult data interpretation for patients close to the limit of contiguous age group ranges. In addition, normal values for a number of lymphocyte subpopulations have not been established to date. Objective: The aim of this study was to develop a model which provides continuous age‐dependent reference values. This model was applied for lymphocyte subpopulations such as naïve and memory T cells as well as their activation profile with diagnostic relevance in children and adults. Study design: A total of 100 blood samples, obtained from 80 healthy children and 20 adults were analysed by means of four colour‐flow cytometry. Continuous age‐dependent reference values were computed based on the residual values in an exponential regression model. Results: We calculated a continuous age‐related regression model for both, absolute cell counts and percentages of CD3⁺CD4⁺ T helper (T_H) cells, CD3⁺CD8⁺ cytotoxic T cells, CD56⁺CD3^? natural killer (NK) cells, CD56⁺CD3⁺ T cells, CD3⁺CD4⁺CD45RA⁺ naïve T_H cells, CD3⁺CD4⁺CD45RO⁺ memory T_H cells, CD3⁺CD8⁺CD45RA⁺CD28⁺ naïve cytotoxic T cells, CD3⁺CD8⁺CD45RO⁺ memory cytotoxic T cells, CD3⁺CD8⁺CD69⁺ early activated cytotoxic T cells and CD3⁺CD8⁺HLA‐DR⁺ late activated cytotoxic T cells, respectively, to obtain reference values. Conclusion: Based on an exponential regression model, the obtained reference values reflect the continuous maturation of lymphocyte subsets during childhood.     

Immunoadsorption of Immunoglobulins Alters Intracytoplasmic Type 1 and Type 2 T Cell Cytokine Production in Patients with Refractory Autoimmune Diseases

Abstract: Intracellular cytokine staining and flow cytometry were used to investigate whether immunoadsorption (IA) of immunoglobulins alters intracytoplasmic cytokine production in CD4⁺ and CD8⁺ T cells from the blood of patients with refractory rheumatoid arthritis (n = 7), membrane proliferative glomerulonephritis (n = 1), and Goodpasture's syndrome (n = 1). Four patients (Group 1) showed severely depressed production of TNF‐α, IL‐2, IFN‐γ, and IL‐4 by CD4⁺ and CD8⁺ T cells and responded to 3 IA sessions with significant increases in CD4⁺TNF‐α⁺, CD4⁺IL‐2⁺, and CD8⁺IL‐2⁺ T cells. Also, a tendency toward increased percentage levels of CD4⁺ T cells producing IFN‐γ or IL‐4 and of CD8⁺ T cells producing either TNF‐α or IFN‐γ was seen, but due to the small number of patients investigated, these differences did not attain statistic significance. Group 2 (n = 5) showed unimpaired intracellular cytokine levels and responded to IA with a heterogeneous pattern of changes in TNF‐α, IL‐2, IFN‐γ, and IL‐4 production, but these alterations were smaller than those in Group 1. The present findings indicate that the extracorporeal removal of immunoglobulins by anti‐IgG or protein A adsorber columns has an impact on T cell immunity and suggest that modulating effects on cellular immune system function are involved in the mode of action of IA.     

Analysis of T lymphocyte-related biomarkers in pancreatic cancer

BackgroundPancreatic cancer remains one of the most lethal cancers.ObjectiveThis study aimed to analyze T cell-related biomarkers and their molecular network in pancreatic cancer.MethodsRNAseq sequencing data and clinical data of pancreatic cancer were obtained from TCGA database. The STromal and Immune cells in MAlignant Tumours using Expression data (ESTIMATE) algorithm was used to screen the DEGs related to the tumor immune cells. The pearson correlation analysis were used to analyze the relationships between DEGs and T cells. Additionally, the T cell-related DEGs were subjected to protein-protein interaction, competing endogenous RNA (ceRNA), and chemical small molecule-target network construction. Furthermore, the prognosis-associated DEGs were screened.ResultsA total of 412 stromal score-associated and 312 immune score-associated DEGs were obtained. From these DEGs, 50 CD4⁺ T cell-related genes and 13 CD8⁺ T cell-related genes were selected. The PPI networks associated with immune cell-related genes were constructed and found that CD22, SELL, and OLR1 had higher degrees in the PPI network. The number of ceRNA regulatory relation pairs obtained from CD4⁺ T cells and CD8⁺ T cells were 59 and 48, respectively. Additionally, both CD4⁺ T cell- and CD8⁺ T cell-related genes predicted 29 small molecules. CXCL9 and GIMAP7 were screened out from CD4⁺ T cell-related genes, which were related with the survival of pancreatic cancer.ConclusionWe mapped T cell-related gene profile in pancreatic cancer and constructed their potential regulatory network.     

Association between CD8+ T‐cell subsets and cardiovascular disease

Background

The findings of experimental studies suggest that the immune system plays a key role in atherosclerosis, but the clinical importance of different immune cells in cardiovascular disease remains poorly characterized. In this study we investigated the association between CD8⁺ T cells and carotid disease as well as development of cardiovascular disease events.

Methods

The study cohort comprised 700 subjects from the cardiovascular arm of the Malmö Diet and Cancer Study. Peripheral blood mononuclear cells, obtained at the 1991–1994 baseline investigation and stored at ?140 °C, were thawed and the different CD8⁺ T‐cell populations analysed by flow cytometry. Baseline carotid intima–media thickness and stenosis were assessed by ultrasonography and clinical events were monitored through validated national registers.

Results

Subjects with a high fraction of CD8⁺ T cells were characterized by decreased cytokine release from activated leucocytes, metabolic signs of insulin resistance and increased incidence of coronary events; hazard ratios (95% confidence intervals) for the second and third tertiles of CD8⁺ T cells were 2.57 (1.16, 5.67) and 2.61 (1.19, 5,71), respectively, in a Cox proportional hazards regression model. Correlations were found between the fraction of CD8⁺CD25⁺ T cells and the degree of carotid stenosis (r = 0.11, P < 0.01), and between the CD8⁺CD56^?IFN‐γ⁺ T‐cell fraction and the degree of stenosis (r = ?0.18, P < 0.005). The association between CD8⁺CD56^?IFN‐γ⁺ T cells and carotid stenosis remained significant after controlling for major cardiovascular disease risk factors.

Conclusion

This study provides prospective clinical evidence for a role of CD8⁺ T cells in cardiovascular disease and suggests the existence of CD8⁺ T‐cell subsets with different pathological functions.

     

A case of bronchial asthma as an immune-related adverse event of pembrolizumab treatment for bladder cancer: A case report

Rationale:Bladder cancer is one of the most common cancers worldwide. The anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab, which is an immune checkpoint inhibitor (ICI), has improved survival in bladder cancer. We report a case of bladder cancer that had a high antitumor effect with anti-programmed cell death PD-1 antibody pembrolizumab, an ICI, but asthma occurred an immune-related adverse event (irAE).Patient concerns:A 70-year-old female patient was diagnosed as unresectable bladder cancer who was indicated for ICI treatment.Diagnosis:After ICI administration as a treatment for bladder cancer, the patient had a grade 3 asthma attack. Cytotoxic T lymphocyte antigen 4 (CTLA-4) in CD4⁺ FOX3⁺ T cells was upregulated in the early phase before the development of asthma attacks. Moreover, T-cell immunoglobulin and mucin domain 3 (TIM-3) was upregulated in all memory T cells among CD4⁺ T cells. However, no change in the expression of TIM-3 was observed in any CD8⁺ T-cell subtype. In contrast, the proportion of CD161^- T helper 17 cell (Th17) cells increased.Interventions:The patient was treated with betamethasone, montelukast, salbutamol nebulization, and a combination of salmeterol (50 μg) and fluticasone (500 μg) (SFC).Outcomes:The patient''s wheezing resolved, and her peak flow rate reached 100% of the predicted value; therefore, the patient continued treatment with SFC and montelukast and was discharged from the hospital.Conclusion:Increases in CTLA-4 and TIM-3 expression in CD4⁺ T cells (not CD8⁺), as well as an increase in Th17 cells, may reflect asthma-related inflammation activity. Immune-related adverse events during immune checkpoint inhibitor administration may be predictive markers of antitumor efficacy.