Role Of CD38 Research Articles

Abstract MP30: The Role of CD20+ B cells in Mediating Hypertension in Preeclampsia during Pregnancy

Pre-eclampsia (PE), new-onset hypertension after the 20 th week of pregnancy alongside other organ dysfunction, endothelial dysfunction, and immune activation. We have previously shown that CD19+ B cell adoptive transfer causes a PE phenotype in athymic nude rats. CD19 is present on all B cells including plasma cells. CD20 is absent from plasma cells but is present on mature B2 and memory B cells. The objective of this study was to determine if CD20+ B cells, excluding plasma cells, cause maternal hypertension, fetal growth restriction, and endothelial dysfunction. Three hundred thousand placental CD20+ B Cells from normal pregnant (NP) or PE patients were isolated by magnetic separation and injected i.p. into nude athymic rats on gestational day (GD) 12. On GD18, carotid catheters were inserted. On GD19, mean arterial pressure (MAP) was measured and blood and tissues were collected. Preproendothelin (PPET) expression was quantified in kidney and placental tissues using RT-PCR. A student’s t-test was used for statistical analysis. Participants whose placental B cells were used in this study had similar age, pre-pregnancy BMI, and diastolic BP on admission. PE participants had elevated systolic BP at admission (135±4 vs 120±4 mmHg) and delivery (139±6 vs 124±3 mmHg) as well as diastolic BP at delivery (79±4 vs 68±2 mmHg). PE participants also had trending decreases in fetal weight (2621±323 vs 3202±102 g) and gestational age (36±1 vs 39±0 weeks) at delivery. MAP increased from 107±4 mmHg (n=8) in the NP recipient rats to 123±2 mmHg (n=8, p<0.01) in the PE recipient rats. Pup and placental weights were unchanged following adoptive transfer. Renal PPET expression increased by 2.595±0.61 fold (ΔΔct) in PE recipient rats (n=7, p<0.05) compared to NP recipient rats (n=7). Placental PPET expression was unchanged following adoptive transfer. CD20+ B cells from women with PE contribute to hypertension and endothelial dysfunction during pregnancy. This data supports the important role of B cells in the development of PE and improves our understanding of the population of B cells responsible for contribution to the disease.

Identification and characterization of circulating and adipose tissue infiltrated CD20+T cells from subjects with obesity that undergo bariatric surgery

T cells play critical roles in adipose tissue (AT) inflammation. The role of CD20+T cell in AT dysfunction and their contributing to insulin resistance (IR) and type 2 diabetes progression, is not known. The aim was to characterize CD20+T cells in omental (OAT), subcutaneous (SAT) and peripheral blood (PB) from subjects with obesity (OB, n = 42), by flow cytometry. Eight subjects were evaluated before (T1) and 12 months post (T2) bariatric/metabolic surgery (BMS). PB from subjects without obesity (nOB, n = 12) was also collected. Higher percentage of CD20+T cells was observed in OAT, compared to PB or SAT, in OB-T1. CD20 expression by PB CD4+T cells was inversely correlated with adiposity markers, while follicular-like CD20+T cells were positively correlated with impaired glucose tolerance (increased HbA1c). Notably, among OB-T1, IR establishment was marked by a lower percentage and absolute number of PB CD20+T cells, compared nOB. Obesity was associated with higher percentage of activated CD20+T cells; however, OAT-infiltrated CD20+T cells from OB-T1 with diabetes displayed the lowest activation. CD20+T cells infiltrating OAT from OB-T1 displayed a phenotype towards IFN-γ-producing Th1 and Tc1 cells. After BMS, the percentage of PB CD4+CD20+T cells increased, with reduced Th1 and increased Th17 phenotype. Whereas in OAT the percentage of CD20+T cells with Th1/17 and Tc1/17 phenotypes increased. Interestingly, OAT from OB pre/post BMS maintained higher frequency of effector memory CD20+T cells. In conclusion, CD20+T cells may play a prominent role in obesity-related AT inflammation.

The role of CD20+ T cells: Insights in human peripheral blood.

CD20+ T cells constitute a small subset of T cells. These are found among CD4+, CD8+, CD4+CD8+, CD4-CD8- T, and TCRγδ+ T cells, and have been poorly characterized. The aim of this study was to characterize peripheral blood (PB) CD20+ T cells and compare them to their PB CD20- T cell counterparts. PB from 17 healthy individuals was collected. The distribution of CD20+ T cells among maturation-associated T cells compartments (naïve, central memory, transitional memory, effector memory, and effector T cells), their polarization, activation status, and expression of immune-regulatory proteins were evaluated by flow cytometry. Their function was also assessed, by measuring IFN-γ, TNF-α, and IL-17 production. Compared with CD20- T cells, CD20+ T cells represent a higher proportion of transitional memory cells. Furthermore, CD20+ T cells display a proinflammatory phenotype, characterized by the expansion of Th1, Th1/17, and Tc1 cell subsets , associated to a high expression of activation (CD25) and exhaustion (PD-1) markers. In addition, the simultaneous production of the proinflammatory cytokines IFN-γ, TNF-α, and IL-17 was also detected in CD4+CD20+ T cells. Our results show that CD20+ T cells are phenotypically and functionally different from CD20- T cells, suggesting that these cells are a distinct subset of T cells.

CD20 + T lymphocytes in isolated Hashimoto’s thyroiditis and type 3 autoimmune polyendocrine syndrome: a pilot study

BackgroundCD20+ T cells represent up to 5% of circulating T lymphocytes. These cells have been shown to produce higher levels of IL-17A and IFN-γ than those of CD20− T lymphocytes. Some reports described the role of CD20+ T cells in autoimmune disorders such as multiple sclerosis and rheumatoid arthritis possibly due to their ability to produce these inflammatory cytokines. This study is aimed at describing the behavior of CD20+ T lymphocytes in the most frequent autoimmune disorder, i.e., Hashimoto’s thyroiditis (HT), presenting isolated or associated to further autoaggressive disorders in a frame of poly-autoimmunity.MethodsThe study group encompasses 65 HT patients: 23 presenting in isolated form (IT) and 42 with an associated non-endocrine autoimmune disorder [16 with chronic atrophic gastritis (CAG), 15 with nonsegmental vitiligo (VIT), and 11 with celiac disease (CD)]. Twenty healthy donors act as control group (HD). Chronic use of interfering drugs, severe or chronic disorders, and pregnancy and lactation were used as exclusion criteria. Whole blood samples (100 µl) were stained with fluorescent-labeled antibodies (anti-CD45, anti-CD3, anti-CD19, anti-CD16, anti-CD56, anti-CD4, anti-CD8, anti-CD20). Red blood cells were then lysed by adding 1 ml of hypotonic buffer, and samples were acquired on a Flow Cytometer.ResultsCD3+CD8+CD20+ T lymphocytes’ percentages, were significantly higher in the whole group of autoimmune patients compared to healthy donors (p = 0.0145). Dividing HT patients based on the type of presentation of autoimmune thyroiditis, CAG group showed the highest percentage of these cells as compared to HD and CD (p = 0.0058). IT patients showed higher percentages of CD3+ CD8+CD20+ cells than those of HD patients although not reaching statistical significance. However, dividing IT group based on thyroid function, hypothyroid patients showed higher CD8+CD20+ cell percentages than those of HD and euthyroid patients (p = 0.0111). Moreover, in IT patients, these cells were negatively correlated with FT4 levels (p = 0.0171; r = −0.4921).ConclusionsThese preliminary findings indicate that CD8+CD20+ T cells are activated in patients with autoimmune thyroiditis and may behave differently according to the presence of poly-autoimmunity and hypothyroidism.

Inhibition of CD38 enzymatic activity enhances CAR-T cell immune-therapeutic efficacy by repressing glycolytic metabolism

Chimeric antigen receptor (CAR)-T therapy has shown superior efficacy against hematopoietic malignancies. However, many patients failed to achieve sustainable tumor control partially due to CAR-T cell exhaustion and limited persistence. In this study, by performing single-cell multi-omics data analysis on patient-derived CAR-T cells, we identify CD38 as a potential hallmark of exhausted CAR-T cells, which is positively correlated with exhaustion-related transcription factors and further confirmed with invitro exhaustion models. Moreover, inhibiting CD38 activity reverses tonic signaling- or tumor antigen-induced exhaustion independent of single-chain variable fragment design or costimulatory domain, resulting in improved CAR-T cell cytotoxicity and antitumor response. Mechanistically, CD38 inhibition synergizes the downregulation of CD38-cADPR -Ca2+ signaling and activation of the CD38-NAD+-SIRT1 axis to suppress glycolysis. Collectively, our findings shed light on the role of CD38 in CAR-T cell exhaustion and suggest potential clinical applications of CD38 inhibition in enhancing the efficacy and persistence of CAR-T cell therapy.

CD38 Deficiency Alleviates Diabetic Cardiomyopathy by Coordinately Inhibiting Pyroptosis and Apoptosis.

Diabetic cardiomyopathy is one of the diabetes mellitus-induced cardiovascular complications that can result in heart failure in severe cases, which is characterized by cardiomyocyte apoptosis, local inflammation, oxidative stress, and myocardial fibrosis. CD38, a main hydrolase of NAD+ in mammals, plays an important role in various cardiovascular diseases, according to our previous studies. However, the role of CD38 in diabetes-induced cardiomyopathy is still unknown. Here, we report that global deletion of the CD38 gene significantly prevented diabetic cardiomyopathy induced by high-fat diet plus streptozotocin (STZ) injection in CD38 knockout (CD38-KO) mice. We observed that CD38 expression was up-regulated, whereas the expression of Sirt3 was down-regulated in the hearts of diabetic mice. CD38 deficiency significantly promoted glucose metabolism and improved cardiac functions, exemplified by increased left ventricular ejection fraction and fractional shortening. In addition, we observed that CD38 deficiency markedly decreased diabetes or high glucose and palmitic acid (HG + PA)-induced pyroptosis and apoptosis in CD38 knockout hearts or cardiomyocytes, respectively. Furthermore, we found that the expression levels of Sirt3, mainly located in mitochondria, and its target gene FOXO3a were increased in CD38-deficient hearts and cardiomyocytes with CD38 knockdown under diabetic induction conditions. In conclusion, we demonstrated that CD38 deficiency protected mice from diabetes-induced diabetic cardiomyopathy by reducing pyroptosis and apoptosis via activating NAD+/Sirt3/FOXO3a signaling pathways.

The role of CD38 in inflammation-induced depression-like behavior and the antidepressant effect of (R)-ketamine

CD38 is involved in immune responses, cell proliferation, and has been identified in the brain, where it is implicated in inflammation processes and psychiatric disorders. We hypothesized that dysfunctional CD38 activity in the brain may contribute to the pathogenesis of depression. To investigate the underlying mechanisms, we used a lipopolysaccharide (LPS)-induced depression-like model and conducted behavioral tests, molecular and morphological methods, along with optogenetic techniques. We microinjected adeno-associated virus into the hippocampal CA3 region with stereotaxic instrumentation. Our results showed a marked increase in CD38 expression in both the hippocampus and cortex of LPS-treated mice. Additionally, pharmacological inhibition and genetic knockout of CD38 effectively alleviated neuroinflammation, microglia activation, synaptic defects, and Sirt1/STAT3 signaling, subsequently improving depression-like behaviors. Moreover, optogenetic activation of glutamatergic neurons of hippocampal CA3 reduced the susceptibility of mice to depression-like behaviors, accompanied by reduced CD38 expression. We also found that (R)-ketamine, which displayed antidepressant effects, was linked to its anti-inflammatory properties by suppressing increased CD38 expression and reversing synaptic defects. In conclusion, hippocampal CD38 is closely linked to depression-like behaviors in an inflammation model, highlighting its potential as a therapeutic target for antidepressant development.

The role of CD38 in ischemia reperfusion injury in cardiopulmonary bypass and thoracic transplantation: a narrative review.

Ischemia reperfusion injury (IRI) is often the underlying cause of endothelium breakdown and damage in cardiac or transplantation operations, which can lead to disastrous post-operative consequences. Recent studies of cluster of differentiation 38 (CD38) have identified its critical role in IRI. Our objective is to provide a comprehensive overview of CD38-mediated axis, pathways, and potential CD38 translational therapies for reducing inflammation associated with cardiopulmonary bypass (CPB) or thoracic transplantation and IRI. We conducted a review of the literature by performing a search of the PubMed database on 2 April 2023. To find relevant publications on CD38, we utilized the MeSH terms: "CD38" AND "Ischemia" OR "CD38" AND "Transplant" OR "CD38" AND "Heart" from 1990-2023. Additional papers were included if they were felt to be relevant but were not captured in the MeSH terms. We found 160 papers that met this criterion, and following screening, exclusion and consensus a total of 36 papers were included. CD38 is most notably a nicotine adenine dinucleotide (NAD)+ glycohydrolase (NADase), and a generator of Ca2+ signaling secondary messengers. Ultimately, the release of these secondary messengers leads to the activation of important mediators of cellular death. In the heart and during thoracic transplantation, this pathway is intimately involved in a wide variety of injuries; namely the endothelium. In the heart, activation generally results in vasoconstriction, poor myocardial perfusion, and ultimately poor cardiac function. CD38 activation also prevents the accumulation of atherosclerotic disease. During transplantation, intracellular activation leads to infiltration of recipient innate immune cells, tissue edema, and ultimately primary graft dysfunction (PGD). Specifically, in heart transplantation, extracellular activation could be protective and improve allograft survival. The knowledge gap in understanding the molecular basis of IRI has prevented further development of novel therapies and treatments. The possible interaction of CD38 with CD39 in the endothelium, and the modulation of the CD38 axis may be a pathway to improve cardiovascular outcomes, heart and lung donor organ quality, and overall longevity.

The NADase CD38 may not dictate NAD levels in brain mitochondria of aged mice but regulates hydrogen peroxide generation

Aging is a time-related functional decline that affects many species. One of the hallmarks of aging is mitochondrial dysfunction, which leads to metabolic decline. The NAD decline during aging, in several tissues, correlates with increase in NADase activity of CD38. Knock out or pharmacological inhibition of CD38 activity can rescue mitochondrial function in several tissues, however, the role of CD38 in controlling NAD levels and metabolic function in the aging brain is unknown. In this work, we investigated CD38 NADase activity controlling NAD levels and mitochondrial function in mice brain with aging. We demonstrate that NADase activity of CD38 does not dictate NAD total levels in brain of aging mice and does not control mitochondrial oxygen consumption nor other oxygen parameters markers of mitochondrial dysfunction. However, for the first time we show that CD38 regulates hydrogen peroxide (H2O2) generation, one of the reactive oxygen species (ROS) in aging brain, through regulation of pyruvate dehydrogenase and alfa-ketoglutarate dehydrogenase, as mitochondria H2O2 leakage sites. The effect may be related to mitochondrial calcium handling differences in CD38 absence. Our study highlights a novel role of CD38 in brain energy metabolism and aging.

Role of CD27 and SAMHD1 and their genetic susceptibility to COVID-19

SARS-CoV-2, which initiated the worldwide COVID-19 epidemic in 2019, has rapidly emerged and spread, resulting in significant public health challenges worldwide. The COVID-19 severity signs and their association with specific genes have been investigated to better comprehend this phenomenon. In this study, several genes were investigated to see whether they correspond with COVID-19 sickness severity.This research aims to determine and evaluate certain gene expression levels associated with the immune system, as these genes were reported to play important roles in immune control during the COVID-19 outbreak. We analyzed two immunity-linked genes: CD27 and SAMHD1 in COVID-19 patients’ samples using RT-PCR, compared them to the samples from recovered, immunized, and healthy individuals. These data were examined to determine the potential relationships between clinical patterns, illness severity, and progression, and SARS-CoV-2 infection immunology.We observed that CD27 gene expression was higher in COVID-19 vaccinated and control groups, but lower in active and recovered COVID-19 patients. On the other hand, SAMHD1 gene expression was elevated in infected and recovered COVID-19 groups. According to our study, the proteins CD27 and SAMHD1 are essential for controlling the immunological response to COVID-19. Changes in their expression levels could increase the susceptibility of patients to severe complications associated with the disease. Therefore, the gene expression level of these proteins could serve as viable prognostic markers for COVID-19.

CD38 regulates ovarian function and fecundity via NAD+ metabolism

Mammalian female reproductive lifespan is typically significantly shorter than life expectancy and is associated with a decrease in ovarian NAD+ levels. However, the mechanisms underlying this loss of ovarian NAD+ are unclear. Here, we show that CD38, an NAD+ consuming enzyme, is expressed in the ovarian extrafollicular space, primarily in immune cells, and its levels increase with reproductive age. Reproductively young mice lacking CD38 exhibit larger primordial follicle pools, elevated ovarian NAD+ levels, and increased fecundity relative to wild type controls. This larger ovarian reserve results from a prolonged window of follicle formation during early development. However, the beneficial effect of CD38 loss on reproductive function is not maintained at advanced age. Our results demonstrate a novel role of CD38 in regulating ovarian NAD+ metabolism and establishing the ovarian reserve, a critical process that dictates a female's reproductive lifespan.

1628-P: Role of CD38 in the Regulation of Muscle Stem Cell Functions in Aged Mice

Skeletal muscle repair and regeneration is a complex process and is known to be delayed with aging, diabetes and obesity. This is in part due to infiltration of inflammatory macrophages which can delay the recovery process. Both macrophages and satellite cells require nicotinamide adenine dinucleotide (NAD+) for their biological functions. Aging-induced decline in NAD+ have been shown to worsen insulin resistance and muscle dysfunction. CD38 is an ectoenzyme that degrades NAD+ and is increased in inflammatory macrophages in aging, obesity and other insulin-resistant states. However, how inhibition of CD38 affects satellite cell functions in aged or obese mice, remains unknown. Here, we utilized aged CD38 knockout mice to assess the role of this protein and NAD+ in the recovery process in injured muscle. CD38 KO mice were found to be resistant to diet-induced obesity and had improved insulin sensitivity. Our data show that genetic deletion of CD38 in aged mice increased NAD+ levels and thus enhanced muscle stem/satellite cells differentiation and promote myogenesis. Deletion of CD38 also resulted in an enhanced number of regenerating myofibers. Furthermore, we found that deletion of CD38 significantly reduces fibrosis of muscle and also improved limb grip strength. Pharmacological inhibition of CD38 in C2C12 myoblasts and ex-vivo primary myoblasts significantly increased NAD+ levels and also enhanced the differentiation of satellite cells into myoblasts and myofibers. We, therefore, examined the rescue effects of 78c (CD38i) on human recombinant CD38 (hCD38) inhibition of muscle stem cells. Administration of hCD38 inhibited expression of MyoD and MyoG in primary myoblasts, while this effect was rescued through 78c treatment. Taken together, these data demonstrate that restoration of NAD+ levels either through genetic deletion/pharmacological inhibition of CD38 can improve muscle stem cell functions and muscle regeneration and might promote muscle regeneration in obesity, type 2 diabetes, and aging. Disclosure A.Nawaz: None. K.Yaku: None. I.Jeelani: None. K.Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care. T.Nakagawa: None.

Deciphering prognostic value of CD22 and its contribution to suppression of proinflammatory cytokines production in patients with IgA nephropathy

BackgroundCD22, mainly expressed in mature B cells, could negatively regulate the function of B cells by binding to sialic acid-positive IgG (SA-IgG). Soluble CD22 (sCD22) is generated by the cleavage of the extracellular domain of CD22 on the membrane surface. However, the role of CD22 in IgA nephropathy (IgAN) remains unknown. MethodsA total of 170 IgAN patients with a mean follow-up of 18 months were included in this study. The sCD22, TGF-β, IL-6 and TNF-α were detected using commercial ELISA kits. SA-IgG were purified to stimulate peripheral blood mononuclear cells (PBMCs) from IgAN patients. ResultsThe plasma levels of sCD22 were lower in IgAN patients in comparison with healthy control. Furthermore, CD22 mRNA levels in PBMCs from patients with IgAN were significantly lower than those of healthy controls. The plasma levels of sCD22 were positively correlated to the mRNA levels of CD22. We found that patients with higher sCD22 levels had a lower level of serum creatinine and a higher level of eGFR on the time of renal biopsy and a higher remission rate of proteinuria and a lower risk of kidney events at the end of follow-up. The logistic regression analysis showed sCD22 was associated with an increased odd of proteinuria remission after being adjusted for eGFR, proteinuria, and SBP. After adjusting for confounding variables, sCD22 was a borderline significant predictor of less kidney composite endpoint. In addition, the sCD22 levels were positively associated with SA-IgG in plasma. The experimental results in vitro showed that addition of SA-IgG enhanced the release of sCD22 in cell supernatant and the phosphorylation of CD22 in PBMCs, further inhibiting the production of IL-6, TNF-α, and TGF-β in cell supernatant in a dose-dependent manner. Pretreatment with CD22-antibody significantly increased the expression of cytokines in PBMCs. ConclusionsThis is the first study to demonstrate that lower plasma soluble CD22 in IgAN patients and high soluble CD22 levels are associated with an increased odd of proteinuria remission and a decreased odd of kidney endpoint. The interaction between CD22 and SA-IgG can inhibit proliferation and inflammation release in PBMCs from IgAN patients.

Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice

Boosting NAD+ levels are considered a promising means to promote healthy aging and ameliorate dysfunctional metabolism. The expression of CD38, the major NAD+-consuming enzyme, is downregulated during thermogenesis in both brown and white adipose tissues (BAT and WAT). Moreover, BAT activation and WAT "browning" were enhanced in Cd38-/- mice. In this study, the role of CD38 in the liver during thermogenesis was investigated, with the liver being the central organ controlling systemic energy metabolism. Wild-type mice and Cd38-/- mice were exposed to cold temperatures, and levels of metabolites and enzymes were measured in the livers and plasma. During cold exposure, CD38 expression was downregulated in the liver, as in BAT and WAT, with a concomitant increase in NAD(H) and a marked decrease in NADPH levels. Glucose-6-phosphate dehydrogenase and the malic enzyme, along with enzymes in the glycolytic pathway, were downregulated, which is in line with glucose-6-P being re-directed towards glucose release. In Cd38-/- mice, the cross-regulation between glycolysis and glucose release was lost, although this did not impair the glucose release from glycogen. Glycerol levels were decreased in the liver from Cd38-/- animals upon cold exposure, suggesting that glyceroneogenesis, as gluconeogenesis, was not properly activated in the absence of CD38. SIRT3 activity, regulating mitochondrial metabolism, was enhanced by cold exposure, whereas its activity was already high at a warm temperature in Cd38-/- mice and was not further increased by the cold. Notably, FGF21 and bile acid release was enhanced in the liver of Cd38-/- mice, which might contribute to enhanced BAT activation in Cd38-/- mice. These results demonstrate that CD38 inhibition can be suggested as a strategy to boost NAD+ and would not negatively affect hepatic functions during thermogenesis.

Therapeutic Potential and Role of CD38 in Cutaneous T-Cell Lymphoma Pathogenesis

Therapeutic Potential and Role of CD38 in Cutaneous T-Cell Lymphoma Pathogenesis

The Role of CD28 and CD8+ T Cells in Keloid Development.

Background: A keloid is a benign skin tumor that extends beyond the initial injury area, and its pathologic mechanism remains unclear. Method: High-throughput sequencing data were obtained from normal skin tissue of patients with keloids (Group N) and healthy controls (Group C). Important genes were mined by bioinformatics analysis and identified by RT–qPCR, Western blotting, immunohistochemistry and immunofluorescence assays. The CIBERSORT algorithm was used to convert gene expression information into immune cell information. Flow cytometry was used to verify the key immune cells. Fluorescence-activated cell sorting coculture and CCK8 experiments were used to explore the effect of CD8+ T cells on keloid-associated fibroblasts. Neural network models were used to construct associations among CD28, CD8+ T cells and the severity of keloids and to identify high-risk values. Result: The expression levels of costimulatory molecules (CD28, CD80, CD86 and CD40L) in the skin tissue of patients with keloids were higher than the levels in healthy people (p < 0.05). The number of CD8+ T cells was significantly higher in Group N than in Group C (p < 0.05). The fluorescence intensities of CD28 and CD8+ T cells in Group N were significantly higher than those in Group C (p = 0.0051). The number and viability of fibroblasts cocultured with CD8+ T cells were significantly reduced compared with those of the control (p < 0.05). The expression of CD28 and CD8+ T cells as the input layer may be predictors of the severity of keloids with mVSS as the output layer. The high-risk early warning indicator for CD28 is 10–34, and the high-risk predictive indicator for CD8+ T cells is 13–28. Conclusions: The abnormal expression of costimulatory molecules may lead to the abnormal activation of CD8+ T cells. CD8+ T cells may drive keloid-associated immunosuppression. The expression of CD28 and CD8+ T cells as an input layer may be a predictor of keloid severity. CD28 and CD8+ T cells play an important role in the development of keloids.

CD28 and chemokine receptors: Signalling amplifiers at the immunological synapse.

T cells are master regulators of the immune response tuning, among others, B cells, macrophages and NK cells. To exert their functions requiring high sensibility and specificity, T cells need to integrate different stimuli from the surrounding microenvironment. A finely tuned signalling compartmentalization orchestrated in dynamic platforms is an essential requirement for the proper and efficient response of these cells to distinct triggers. During years, several studies have depicted the pivotal role of the cytoskeleton and lipid microdomains in controlling signalling compartmentalization during T cell activation and functions. Here, we discuss mechanisms responsible for signalling amplification and compartmentalization in T cell activation, focusing on the role of CD28, chemokine receptors and the actin cytoskeleton. We also take into account the detrimental effect of mutations carried by distinct signalling proteins giving rise to syndromes characterized by defects in T cell functionality.

Research progress in the role of CD38 in clinical tumor treatment.

Tumor is one of the ten leading causes of death in the world. Traditional tumor treatments include surgery, radiation therapy, and chemotherapy. With the development of immune checkpoint blockade therapy targeting the programmed death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis, the number of cancers in solid tumors has increased. Changes in the immunometabolic microenvironment have been shown to be important regulators of innate suppression of immune cell function and acquired resistance to immunotherapy. As a new target, CD38 is an enzyme that produces immunosuppressive metabolites (such as adenosine), which can be used in combination with immunotherapy to improve the clinical efficacy of tumor therapy, and can also be used as an indicator for understanding tumor immunotherapy response.

Compound 78c exerts a therapeutic effect on collagen-induced arthritis and rheumatoid arthritis.

Many studies have found that CD38 expression is increased in rheumatoid arthritis (RA), an autoimmune disease in which immune tolerance is dysregulated. Inhibition of CD38 expression or activity can significantly alleviate collagen-induced arthritis (CIA), a well-known animal model used for the study of RA. This study aimed to confirm the therapeutic effect of 78c, a specific inhibitor of CD38, and the role of CD38+ NK cells in immune imbalance in RA. CIA mice were injected with 78c to observe the therapeutic effect. CD38+ NK cells were extracted from human peripheral blood and treated with 78c. The pretreated NK cells were co-cultured with CD4+ T cells. We found that 78c significantly suppressed joint inflammation; reduced the levels of B cells, IL-6 and TNF-α; and increased the levels of IL-10, energy metabolism and spontaneous movement in CIA mice. 78c treatment also increased Treg cell numbers and decreased the Th1/Th2 ratio in the CIA model animals. Moreover, the proportion of CD38+ NK cells was increased in the CIA mice and significantly decreased following 78c treatment. Human CD4+ T cells that were co-cultured with 78c-pretreated CD38+ NK cells differentiated into more Treg cells and had lower Th17/Treg and Th1/Th2 ratios than CD4+ T cells co-cultured with CD38+ NK cells without the pretreatment. Transcriptomic analyses demonstrated that 78c changed expression pro les in CD38+ NK cells. These results suggested that 78c could be used for the treatment of RA and CIA as it alleviates the inhibitory effect of CD38+ NK cells on CD4+ T cell differentiation to Treg cells to restore immune balance.

Abstract WP16: Characterizing Cd38 Expression And Activity In The Brain Of Spontaneously Hypertensive Stroke Prone Rats

Introduction: CD38 is an ectoenzyme that is the main source of age dependent decrease in NAD + levels. Its role in cerebral small vessel disease (cSVD) is unknown. We hypothesize that CD38 is over-expressed and activated in spontaneously hypertensive stroke-prone rat (SHRSP), a model of human cSVD. Methods: 20 SHRSP and 20 age matched male Wistar Kyoto control rats (WKY) were studied. Systolic blood pressure (SBP) was measured weekly using tail-cuff plethysmography. Half of the groups were euthanized at 7 weeks of age (Wks) and the remaining rats were followed until 24 Wks. Routine histology and immunohistochemistry (IHC) were performed for nitric oxide synthase (NOS) subtypes, superoxides (DHE), NO (DAF), and NADPH. IHC was used to detect CD38 expression and co-staining determined expression on endothelial cells (eNOS), astrocytes (GFAP), microglia (Iba1), T cells (CD3), macrophages (CD68), neutrophils (MPO) and neurons (Neuon). CD38 activity was detected in the brain homogenate by using a substrate analog of NAD + with measurement of its conversion to the strongly fluorescent product (ε-ADPR). Results: Compared to WKY, SHRSP developed hypertension between (9 -12) Wks and sustained it afterwards (SBP: 19 Wks: WKY 142.5±11.8 mmHg vs SHRSP 180.3±12.8 mmHg, P&lt;0.0001). At 24 Wks, SHRSP showed histological evidence of cSVD including microbleed, enlarged perivascular spaces, and lipohyalinosis. Compared to WKY, CD38 expression was increased in SHRSP brain (7 Wks: 102.6%, P=0.011, 24 Wks: 83.2%, p=0.0077). CD38 activity was also significantly higher in SHRSP (7 Wks: 11.8%, p=0.012, 24 Wks: 20.2%, p=0.0065). We identified CD38 expression on endothelial cells, astrocytes and microglia. In comparison to WKY, SHRSP showed lower levels of NADPH (7 Wks: 22.3%, p=0.029, 24 Wks: 65.5%, p=0.0065), NO (7 Wks: 39.3% p=0.0008, 24 Wks: 36%, p=0.04), endothelial NOS (7 Wks: 57.5%, p=0.02, 24 Wks: 50.6%, p=0.01) and higher superoxide (7 Wks: 131%, p&lt;0.0001, 24 Wks: 163%, p&lt;0.0001). Conclusions: The brain of SHRSP shows evidence for elevated CD38 activity and expression with associated oxidative stress, depletion of NADPH and eNOS dysfunction compared to normotensive WKY. These results suggest the potential role of CD38 based therapeutics in future management of human cSVD.