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Targeting CD100 by antibody blockade is a potential therapeutic strategy for cancers, but the functional effects on T cells following blockade of this immune activating molecule are rarely considered. Indeed, CD100 is highly expressed in T cells and anti-CD100 antibodies play a role during T cell proliferation; however, the outcome varies from different studies and the underlying mechanism is still unclear. To address this, monoclonal antibody clones directed against CD100 were evaluated. In their soluble form, four of these antibodies significantly reduced the expansion of T cells in the presence of bead-bound anti-CD3/CD28, either in total peripheral blood mononuclear cell or purified T cell culture systems. Similar inhibition was seen when blocking CD100-CD72 interaction by soluble anti-CD72 instead of anti-CD100 antibodies. Conversely, restoring the interaction by CD72-Fc eliminated the soluble anti-CD100-induced inhibitory effect. Taken together, these results reveal that T cell proliferation is regulated by CD100 interaction with CD72. They further establish an system to evaluate the inhibitory effect of anti-CD100 antibodies on T cells, to which attention should be paid in clinical trials in order to avoid potential side effects.

Airway epithelial cells (AECs) participate in allergic airway inflammation by producing mediators in response to allergen stimulation. Whether ovalbumin (OVA) challenge promotes exosome release from AECs (OVA‐challenged AEC‐derived exosomes (OAEs)), thereby affecting airway inflammation, as well as the underlying mechanisms, is unknown. Our study showed that AECs released an increased number of exosomes after OVA challenge, and the expression of Plexin B2 (PLXNB2; a natural CD100 ligand) was increased by a massive 85.7‐fold in OAEs than in PBS‐treated AEC‐derived exosomes (PAEs). CD100+F4/80+ macrophages engulfed OAEs to trigger the transcription of pro‐inflammatory chemokines and cytokines. Plxnb2 transcripts increased in asthmatic lungs, and similarly, PLXNB2 protein was highly enriched in exosomes purified from asthmatic bronchoalveolar lavage (BAL) fluid. Furthermore, aspiration of PLXNB2 or OAEs increased the recruitment of lung neutrophils, monocytes, eosinophils and dendritic cells in OVA‐challenged mice. Mechanistically, OAE aspiration enhanced the cleavage of CD100 by MMP14, which manifested as an increase in the soluble CD100 (sCD100) level in BAL fluid and lung homogenates. Knockdown of Mmp14 in macrophages prevented the cleavage of CD100 and reduced Ccl2, Ccl5 and Cxcl2 transcription. These data indicate that PLXNB2‐containing OAEs aggravate airway asthmatic inflammation via cleavage of CD100 by MMP14, suggesting potential therapeutic targets of OAE‐mediated asthma exacerbations.

CD100/SEMA4D, a member of the Semaphorin family, is a transmembrane glycoprotein that regulates neurogenesis, immune modulation, and angiogenesis, with its immunoregulatory roles having attracted considerable attention. It is dynamically expressed on the surface of diverse immune cells—including T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells—with expression levels modulated by cellular activation states. CD100 exists in two functional forms: membrane-bound CD100 (mCD100) and soluble CD100 (sCD100) generated via proteolytic cleavage. Recent studies have highlighted its critical involvement in viral infectious diseases. This review systematically summarizes the molecular characteristics, expression patterns, and regulatory functions of CD100 on different immune cells, and discusses its role in viral infectious diseases and its clinical application potential.

Background The glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes of mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signalin receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes. Methods The glucose tolerance test and insulin tolerance test in sema4D -/- and sema4D +/+ mice were compared before and after streptozotocin (STZ) injection; the expression of GLUT2 content on the membrane surface of both groups was verified by Western blot. Then, the levels of insulin and C-peptide in the serum of the two groups of mice after STZ injection were measured by ELISA; the differentially expressed mRNAs in the liver of the two groups of mice were analyzed by transcriptomic analysis; then the differences in the expression of GLUT2, glycogen, insulin and glucagon in the two groups of mice were compared by tissue section staining. Finally, metabolomics analysis was performed to analyze the metabolites differentially expressed in the two groups of mice. Key findings First, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after STZ injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis. Conclusions Thus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis.

Background C D100 is an immune semaphorin family member that highly expressed on T cells, which take part in the development of acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) are important mediators for membrane-bound CD100 (mCD100) shedding from T cells to generate soluble CD100 (sCD100), which has immunoregulatory effect on T cells. The aim of this study was to investigate modulatory role of CD100 on CD8 + T cell activity in AMI patients. Methods Peripheral sCD100 and MMP-2 level, as well as mCD100 level on T cells was assessed in patients with stable angina pectoris (SAP), unstable angina pectoris (UAP), and AMI. The regulatory function of MMP-2 on mCD100 shedding, sCD100 formation, and cytotoxicity of CD8 + T cells was analyzed in direct and indirect contact co-culture system. Results AMI patients had higher peripheral sCD100 and lower mCD100 expression on CD8 + T cells in comparison with SAP, UAP, and controls. CD8 + T cells in AMI patients showed elevated direct cytotoxicity, enhanced cytokine production, and increased perforin/granzyme B secretion. Recombinant sCD100 stimulation promoted cytolytic function of CD8 + T cells in controls and AMI patients. Furthermore, AMI patients also had elevated circulating MMP-2 level. Recombinant MMP-2 stimulation induced mCD100 shedding from CD8 + T cells and sCD100 generation, resulting in enhancement of CD8 + T cell cytotoxicity in AMI patients. Conclusion Up-regulation of MMP-2 might contribute to elevation of mCD100 shedding and sCD100 formation, leading to increased cytotoxicity CD8 + T cells in AMI patients.

Diabetes is a condition that causes delayed wound healing and results in chronic wounds. CD100 has been reported to promote and induce potent and obvious angiogenesis both in vivo and in vitro studies, the absence of which are a main cause of the diabetic chronic wound. In the present study, we investigated the effects of application of soluble CD100 on wound healing in diabetic mice. Four 5-mm full-thickness dermal wounds were made on each male db/db mouse. 12 mice from CD100 group were subcutaneously injected with 250 ng of CD100 (50 µl) per wound, in addition, 12 mice were injected with the same volume phosphate-balanced solution as the control. The animals were treated every other day until the wounds healed completely. Images were obtained to calculate the area ratio of the original area. HE and Masson’s trichrome staining were used for histological examination. Collagen remodeling, angiogenesis and wound bed inflammation were evaluated by immunohistochemical staining and western blot. We demonstrated that CD100 had distinct functions during the wound healing process. Histological and western blotting analysis showed a more organized epithelium and dermis, more collagen fibers, higher angiogenesis and lower inflammation in the CD100 group than in the PBS group. These findings suggest that CD100 may accelerate wound healing in diabetic mice by promoting angiogenesis in the wound and by reducing the inflammatory response.

CD100, also known as Sema4D, is an immune semaphorin constitutively expressed on natural killer (NK) cells and T cells. As an immune activation molecule, CD100 has important immunoregulatory effects on NK functions by enhancing the interactions between NK cells and target cells. The aim of this study was to investigate whether hepatitis C virus (HCV) infection affects CD100 expression, and whether interferon-α treatment enhances NK killing activity to facilitate HCV clearance CD100. Expression of CD100 on NK cells was evaluated by flow cytometry in patients with chronic HCV infection, with or without pegylated interferon-α-based therapy. NK cell cytotoxicity and interferon (IFN)-γ production were measured by flow cytometry upon culturing the NK cells with K562 and Huh7.5 or HCV JFH-1-infected Huh7.5 cells. The frequency of CD100 NK cells in HCV-infected individuals was slightly suppressed compared to healthy subjects. IFN-α treatment could significantly upregulate CD100 expression, which was confirmed by studies using peripheral blood mononuclear cells cocultured with HCV-expressing Huh7.5 cells or IFN-α. Importantly, the expression of CD100 on NK cells from HCV patients was inversely associated with the HCV-RNA levels in the early phase of IFN-α therapy, and the IFN-α upregulated CD100 led to an enhanced NK killing activity through ligations with its receptors plexin-B1/B2 on target cells. These results implied a novel mechanism by which IFN-α enhanced CD100/Plexin-B1/B2 interaction plays an important role in promoting NK functions in patients with chronic hepatitis C.

目的 观察肝细胞癌(HCC)患者外周血CD100的变化，探讨CD100对HCC患者T淋巴细胞功能的调控作用。 方法 前瞻性选择2020年4月—2021年7月在空军军医大学第二附属医院就诊的HCC患者57例和对照者22例。采集抗凝外周血，分离血浆和外周血单个核细胞(PBMC)，酶联免疫吸附试验检测血浆可溶型CD100(sCD100)水平，流式细胞术检测CD4+和CD8+T淋巴细胞表面膜型CD100(mCD100)表达。使用重组人CD100刺激HCC患者PBMC，细胞计数试剂盒-8法检测细胞增殖，流式细胞术检测不同类型辅助性T淋巴细胞(Th细胞)和杀伤性T淋巴细胞(Tc细胞)比例，酶联斑点吸附试验检测甲胎蛋白(AFP)特异性CD8+T淋巴细胞分泌穿孔素和颗粒酶B水平。纯化HCC患者CD8+T淋巴细胞，使用重组人CD100刺激后与HepG2细胞共培养，检测AFP特异性CD8+T淋巴细胞诱导HepG2细胞死亡水平。符合正态分布的计量资料两组间比较采用t检验或配对t检验；不符合正态分布的计量资料两组间比较采用Mann-Whitney U秩和检验。计数资料两组间比较采用χ2检验。 结果 HCC组血浆sCD100水平低于对照组[(2.73±0.58)ng/mL vs(3.33±0.84)ng/mL，t=3.584，P＜0.001]。HCC组CD4+T淋巴细胞中mCD100阳性细胞比例(55.57%±11.33% vs 43.67%±6.40%，t=4.636，P＜0.001)和mCD100平均荧光强度(294.80±74.01 vs 255.00±74.01，t=2.126，P=0.037)均高于对照组。HCC组CD8+T淋巴细胞中mCD100阳性细胞比例(48.65%±7.71% vs 41.74%±4.77%，t=3.914，P＜0.001)和mCD100平均荧光强度(289.20±89.30 vs 246.10±60.73，t=2.082，P=0.041)亦均高于对照组。HCC患者PBMC增殖、T淋巴细胞比例在经CD100刺激和无CD100刺激之间差异无统计学意义(P值均＞0.05)。经CD100刺激后，HCC患者PBMC中CD4+IFNγ+Th1细胞、CD4+IL-17A+Th17细胞、CD4+IL-22+Th22细胞、CD8+IFNγ+Tc1细胞比例均高于无CD100刺激(t值分别为2.608、5.663、4.113

Background Despite improvements in antimicrobial therapy and supportive care, sepsis is still a major public health issue. Recently, CD100 and its receptor in the immune system CD72 were shown to play a major role in immune regulation. The purpose of this study was to investigate the expression and clinical correlations of CD72 and CD100 on circulating lymphocytes of septic patients. Methods In total, 24 healthy controls and 54 septic patients were enrolled in this study. Considering the focus of the current study was on the immunosuppressive phase of sepsis, blood samples of patients were collected at days 3–4 after the onset of sepsis. The levels of CD72 and CD100 expression on circulating lymphocytes were measured by flow cytometry and serum IL-6, IL-10, and immunoglobulin M levels were determined by enzyme-linked immunosorbent assay. Results Our results showed that the levels of CD100 expression on T cells and CD72 expression on B cells were significantly lower in septic patients. Similarly, a significant decrease in the expression levels of CD72 and CD100 was observed in non-survivors compared with survivors. In addition, the reduction of immunoglobulin M levels and lymphocyte counts were correlated with the low CD72 and CD100 expression levels. Multivariate logistic regression analysis showed that the percentage of CD100 + /CD8 + T cells and CD72 + /CD19 + B cells were independent predictors of 28-day mortality in septic patients. Simultaneously, the receiver operating characteristic curve analysis showed that the combination of the percentage of CD100 + /CD8 + T cells and sequential organ failure assessment score had the best predictive value of mortality risk. Conclusions Our study demonstrated that the decrease of the levels of CD72 and CD100 expression on circulating lymphocytes after 3–4 days of sepsis had a close correlation of the 28-day mortality of septic patients. Thus, CD72 and CD100 are promising biomarkers for assessing the prognosis of patients with sepsis. Trial registration Peripheral blood lymphocytes analysis detects CD72 and CD100 alteration in trauma patients; ChiCTR1900026367; Registered 4 October 2019; http://www.chictr.org.cn .

Soft tissue sarcomas (STSs) are a heterogeneous group of mesenchymal tumors of >50 subtypes. However, STSs represent <1% of types of cancer. Despite this low frequency, the disease is aggressive and treatment, when possible, is based on traditional chemotherapies. A number of cases of resistance to adjuvant therapies have been reported. Metastases are commonly identified in STS patients during diagnosis and the development of effective clinical parameters is crucial for correct management of the disease. The use of biological markers in cancer is a useful tool to determine patient prognosis. Ki-67 is a protein marker for proliferation of somatic cells and is widely used in prognostic studies of various types of tumor, including STSs. Cluster of differentiation 100 (CD100) is a member of the semaphorin family. The family was initially described as axon guidance molecules important for angiogenesis, organogenesis, apoptosis and neoplasia. CD100 was previously utilized as a prognostic factor in tumors and also in STSs. In the present study, protein expression of Ki-67 and CD100 was analyzed by immunohistochemistry in samples of STS patients of the Barretos Cancer Hospital (Barretos, Brazil) to establish prognostic criteria of the disease. Results demonstrate a correlation between CD100 expression and poor prognosis, consistent with a previous study. Moreover, the expression of Ki-67 was identified to correlate with presence of local or locoregional recurrence. To the best of our knowledge, no large casuistic study has revealed this correlation between Ki-67 and local recurrence in STSs. The use of Ki-67 and CD100 as markers in clinical pathological analysis may be suitable as a prognostic criterion in disease progression.