T cell interactions with microglia in immune-inflammatory processes of ischemic stroke

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

Primary duodenal T/histiocyte-rich large B-cell lymphoma complicated with obstructive jaundice:A case report and review of literature

BACKGROUND T/histiocyte-rich large B-cell lymphoma(T/HRBCL)is a highly aggressive subtype of diffuse large B-cell lymphoma characterized histologically by the presence of a few neoplastic large B cells amidst an abundant background of reactive T lymphocytes and/or histiocytes.T/HRBCL commonly affects the lymph nodes,followed by extranodal sites,such as the spleen,liver,and bone marrow,with rare occurrences in the gastrointestinal tract.Primary gastrointestinal T/HRBCL lacks specific clinical and endoscopic manifestations,and it is difficult to differentiate from inflammatory diseases,nodular lymphocyte predominant Hodgkin lymphoma,and other diseases on a histological basis,thereby hindering early diagnosis.CASE SUMMARY A 63-year-old man was hospitalized with a one-month history of jaundice and weight loss of approximately 3 kg.Laboratory tests revealed increased hepatic parameters in a cholestatic pattern and elevated carbohydrate antigen 19-9 levels.An abdominal computed tomography scan revealed a low-density mass within the descending duodenum and dilation of the bile and pancreatic ducts.He was clinically diagnosed with a duodenal tumor.During surgery,a 7.0 cm×8.0 cm mass was identified within the descending duodenum,so pancreaticoduodenectomy and cholecystectomy were performed.Following operative biopsy,the tumor was diagnosed as primary duodenal T/HRBCL.The patient refused postoperative chemotherapy and died four months after surgery.CONCLUSION Primary duodenal T/HRBCL is an extremely rare and highly aggressive malignancy.The initial treatment strategies should be based on the original site of the tumor,the disease stage,and the patient's physical condition.Chemotherapy-based comprehensive treatment is still the main treatment method for primary gastrointestinal T/HRBCL.

盐酸青藤碱抑制急性T淋巴细胞白血病CEM细胞株的作用及转录组学分析

背景:盐酸青藤碱有抗多种肿瘤的作用,但目前尚不清楚盐酸青藤碱对急性T淋巴细胞白血病的作用。目的:探讨盐酸青藤碱对急性T淋巴细胞白血病CEM细胞的抑制作用。方法:应用不同浓度(0.5,1,2,4 mmol/L)盐酸青藤碱处理CEM细胞,CCK-8检测细胞增殖抑制率并计算IC50;倒置显微镜和吉姆萨染色观察CEM细胞形态变化;利用RNA-Seq测序分析差异基因表达并进行生物信息学分析。结合转录组测序结果,流式细胞术检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞凋亡率;Western blot检测不同浓度(1,2,4 mmol/L)盐酸青藤碱作用后CEM细胞中Bcl-2、Bax、Caspase-9蛋白的表达。结果与结论:①盐酸青藤碱呈剂量和时间依赖性地抑制CEM细胞生长;②盐酸青藤碱干预后CEM细胞数量下降,核固缩;③RNA-seq测序筛出53个异常表达基因,基因本体分析主要富集在细胞过程、细胞解剖实体与粘连关系等,信号通路分析与肿瘤相关的是细胞凋亡;④盐酸青藤碱呈剂量依赖性地促进CEM细胞凋亡;⑤盐酸青藤碱上调CEM细胞中Bax、Caspase-9蛋白表达,下调Bcl-2蛋白表达。由此可见,盐酸青藤碱可诱导CEM细胞凋亡从而抑制细胞增殖,可能与其上调Bax和Caspase-9蛋白表达,以及下调Bcl-2蛋白表达有关。

血管免疫母细胞性T细胞淋巴瘤临床特征及预后分析

目的:探讨血管免疫母细胞性T细胞淋巴瘤(AITL)患者的临床特征及预后影响因素。方法:回顾性分析2011至2021年在新疆医科大学第一附属医院血液病中心诊治的42例AITL患者临床资料,使用Kaplan-Meier方法计算患者生存率及无进展生存率,log-rank方法进行组间比较。结果:42例患者以老年人为主,中位发病年龄66(22-80)岁,其中25例为男性。38例Ann Arbor分期III-IV期,23例伴有B组症状,34例IPI中高危及高危。起病临床表现以无痛性淋巴结肿大为主(31例),可伴多浆膜腔积液(24例)、发热(17例)、皮疹(11例)和贫血(15例)。18例病理组织活检显示EBV阳性,28例Ki-67≥40%,6例伴发EBV血症。42例患者中位生存时间为12(1-121)个月,3年预估生存率为37.6%,无进展生存率为26.1%。单因素分析结果显示,白介素-6升高、合并多浆膜腔积液的患者生存率更低。结论:AITL起病时临床表现多样,侵袭性高,预后差,常规化疗远期预后不佳。高白介素-6水平、伴有多浆膜腔积液是影响患者预后的不良因素。

血清Tim-3、Galectin-9对重度创伤性脑损伤患者并发急性呼吸窘迫综合征的预测价值

目的探讨血清T细胞免疫球蛋白黏蛋白分子-3(Tim-3)、半乳糖凝集素-9(Galectin-9)对重度创伤性脑损伤(TBI)患者并发急性呼吸窘迫综合征(ARDS)的预测价值。方法选取2020年1月至2023年12月郑州大学第一附属医院收治的180例重度TBI患者作为研究对象,根据受伤后1周内是否发生ARDS分为ARDS组(n=62)和非ARDS组(n=118)。比较两组患者血清Tim-3、Galectin-9水平;采用受试者工作特性(ROC)曲线评估血清Tim-3、Galectin-9对重度TBI患者并发ARDS的预测价值;采用二分类Logistic逐步回归分析探讨重度TBI患者并发ARDS的影响因素。结果ARDS组血清Tim-3、Galectin-9水平高于非ARDS组(P<0.05)。血清Tim-3、Galectin-9及二者联合预测重度TBI患者并发ARDS的曲线下面积(AUC)(95%CI)分别为0.786(0.716-0.855)、0.735(0.652-0.818)、0.835(0.775-0.895),截断值分别为264.24 ng/mL、8.06 ng/mL,特异度分别为0.831、0.788、0.763,灵敏度分别为0.613、0.626、0.742。ARDS组年龄≥60岁、合并休克、机械通气时间≥5d、ICU住院时间≥14d所占的比例均大于非ARDS组,入院时格拉斯哥昏迷量表(GCS)评分、氧合指数(OI)低于非ARDS组,降钙素原(PCT)水平高于非ARDS组(P<0.05)。入院时GCS评分低(OR=0.727,95%CI:0.543-0.973)、OI低(OR=0.957,95%CI:0.932-0.983)、合并休克(OR=9.259,95%CI:3.183-26.937)、Tim-3水平升高(OR=7.110,95%CI:2.738-18.468)、Galectin-9水平升高(OR=7.063,95%CI:2.736-18.230)是重度TBI患者并发ARDS的独立危险因素(P<0.05)。结论血清Tim-3、Galectin-9水平升高与重度TBI患者并发ARDS密切相关,两指标可作为预测重度TBI患者并发ARDS的生物标记物。

养阴润肺汤对肺阴亏虚型肺结核患者的疗效及对外周血调节性T细胞、树突状细胞亚群的影响

目的:探讨养阴润肺汤对肺阴亏虚型肺结核患者的疗效及对外周血调节性T(Treg)细胞及树突状(DC)细胞亚群的影响。方法:选取84例肺阴亏虚型肺结核患者随机分为2组,对照组采取常规西药治疗,研究组在此基础上给予养阴润肺汤治疗,2组均治疗6个月。对比2组治疗前后的症状评分、临床疗效,治疗前后外周血Treg细胞、DC细胞亚群变化及治疗期间的不良反应发生率。结果:治疗后2组症状评分均降低(P<0.05),治疗后研究组咳嗽、咽干、盗汗、潮热症状评分分别为(1.55±0.28)分、(1.46±0.27)分、(1.09±0.22)分、(0.88±0.16)分,均低于对照组的(1.73±0.34)分、(1.59±0.29)分、(1.27±0.26)分、(1.02±0.20)分,差异有统计学意义(P<0.05);研究组总有效率为92.86%,高于对照组的71.43%,差异有统计学意义(P<0.05);治疗后2组外周血Treg细胞水平均降低(P<0.05),且研究组为(2.16±0.42)%,低于对照组的(2.47±0.45)%,差异有统计学意义(P<0.05);治疗后2组DC1、DC2细胞水平均升高(P<0.05),且研究组分别为(0.66±0.13)%、(0.49±0.09)%,高于对照组的(0.59±0.11)%、(0.43±0.08)%,差异有统计学意义(P<0.05);2组治疗期间不良反应发生率比较,差异无统计学意义(P>0.05)。结论:养阴润肺汤能改善肺阴亏虚型肺结核患者的临床症状、调节外周血Treg细胞、DC细胞亚群水平,高效且安全。

基于TRM细胞探讨刺络放血对咪喹莫特诱导的复发型银屑病小鼠的影响及作用机制

目的:基于组织常驻记忆性T细胞(tissue resident memory T cells,T_(RM))探讨刺络放血对咪喹莫特诱导的复发型银屑病小鼠的影响及作用机制。方法:采用背部涂抹咪喹莫特乳膏(Imiquimod,IMQ)二次诱导的方法建立复发型银屑病模型。将实验随机分为分为正常对照组、模型组、刺络放血组、阳性对照组4组,每组6只C57BL/6小鼠,造模后刺络放血组小鼠在背部皮损夹脊穴区域进行刺络放血,阳性对照组小鼠在背部皮损区域均匀涂抹卡泊三醇软膏,正常对照组、模型组小鼠只抓取,不治疗,共治疗6 d。记录各组小鼠背部皮肤表现并进行银屑病面积与严重程度指数(PASI)评分;取各组小鼠背部皮肤HE染色法观察皮肤组织形态表现并行表皮厚度测量,免疫组化及流式细胞术检测各组小鼠背部皮肤组织CD_(8)^(+)T_(RM)与CD_(69)表达。结果:与正常对照组相比,模型组小鼠明显可见红斑、鳞屑、皮肤增厚等表现,PASI评分显著升高,病理切片可见角化过度、炎性细胞浸润、局部出血及表皮层明显增厚(P<0.01);与模型组相比,刺络放血组小鼠红斑、鳞屑、皮肤增厚等表现均减轻,PASI评分降低,病理切片角化过度、炎性细胞浸润、局部出血程度减轻,表皮层增厚减轻(P<0.05);刺络放血组与阳性对照组比较,差异无统计学意义(P>0.05)。与正常对照组相比,模型组小鼠背部皮肤组织CD_(8)^(+)T_(RM)及CD_(69)阳性细胞数显著增多(P<0.01);与模型组相比,刺络放血组小鼠背部皮肤组织CD_(8)^(+)T_(RM)及CD_(69)阳性细胞数有所减少(P<0.05);刺络放血组与阳性对照组比较,差异无统计学意义(P>0.05)。结论:刺络放血可能通过抑制机体T_(RM)细胞的表达起到改善银屑病的作用。

Subpopulations of regulatory T cells are associated with subclinical atherosclerotic plaques,levels of LDL,and cardiorespiratory fitness in the elderly

Background:Atherosclerosis forms the pathological basis for the development of cardiovascular disease.Since pathological processes initially develop without clinically relevant symptoms,the identification of early markers in the subclinical stage plays an important role for initiating early interventions.There is evidence that regulatory T cells(Tregs)are involved in the development of atherosclerosis.Therefore,the present study aimed to identify and investigate associations with Tregs and their subsets in a cohort of healthy elderly individuals with and without subclinical atherosclerotic plaques(SAP).In addition,various lifestyle and risk factors,such as cardiorespiratory fitness,were investigated as associated signatures.Methods:A cross-sectional study was performed in 79 participants(male:n=50;age=63.6±3.7 years;body mass index=24.9±3.1 kg/m2;mean±SD)who had no previous diagnosis of chronic disease and were not taking medication.Ultrasound of the carotids to identify SAP,cardiovascular function measurement for vascular assessment and a cardiorespiratory fitness test to determine peak oxygen uptake were performed.Additionally,tests were conducted to assess blood lipids and determine glucose levels.Immunophenotyping of Tregs and their subtypes(resting(rTregs)and effector/memory(mTregs))was performed by 8-chanel flow cytometry.Participants were categorized according to atherosclerotic plaque status.Linear and logistic regression models were used to analyze associations between parameters.Results:SAP was detected in a total of 29 participants.The participants with plaque were older(64.8±3.6 years vs.62.9±3.5 years)and had higher peripheral systolic blood pressure(133.8±14.7 mmHg vs.125.8±10.9 mmHg).The participants with SAP were characterized by a lower percentage of rTregs(28.8%±10.7%vs.34.6%±10.7%)and a higher percentage of mTregs(40.3%±14.7%vs.30.0%±11.9%).Multiple logistic regression identified age(odds ratio(OR)=1.20(95%confidence interval(95%CI):1.011.42))and mTregs(OR=1.05(95%CI:1.021.10))as independent risk factors for SAP.Stepwise linear regression could reveal an association of peak oxygen uptake(β=0.441),low-density lipoprotein(LDL)(β=0.096),and SAP(β=6.733)with mTregs and LDL(β=0.104)with rTregs.Conclusion:While at an early stage of SAP,the total proportion of Tregs gives no indication of vascular changes,this is indicated by a shift in the Treg subgroups.Factors such as serum LDL or cardiopulmonary fitness may be associated with this shift and may also be additional diagnostic indicators.This could be used to initiate lifestyle-based preventive measures at an early stage,which may have a protective effect against disease progression.

Imbalance of Circulating Follicular Regulatory and Follicular Helper T Cell Subpopulations Is Associated with Disease Progression and Serum CYFRA 21-1 Levels in Patients with Non-small Cell Lung Cancer

Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.

Th17细胞对MPTP诱导的帕金森病模型小鼠神经退变和神经炎症的影响

目的探究辅助性T细胞17(Th17)对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病(PD)模型小鼠神经退变及神经炎症的影响。方法选取C57BL/6小鼠48只,随机分为三组,腹腔注射生理盐水制备对照组,腹腔注射MPTP制备PD模型组,尾静脉注射Th17细胞的PD模型小鼠作为Th17组,每组16只。分别检测各组小鼠的行为学变化;免疫组织化学法检测小鼠中脑黑质的渗漏情况;免疫组织化学法和Western Blot法检测小鼠中脑黑质部位酪氨酸羟化酶(TH)阳性神经元数目变化及TH蛋白表达情况。结果PD模型组小鼠中脑黑质部位的荧光渗漏表现最明显;进一步观察发现,PD模型组小鼠纹状体部位有少量的荧光渗漏,皮质部位没有明显的荧光渗漏;对照组与PD模型组荧光渗漏区域相对荧光强度比较,差异有统计学意义(P<0.01)。在旷场实验中,与对照组相比,PD模型组小鼠移动距离、跨格数目减少,平均速度降低;Th17组小鼠移动距离、跨格数目更少,平均速度更低。在转棒实验中,与对照组相比,PD模型组小鼠在转棒上的潜伏时间缩短,Th17组小鼠的潜伏时间进一步缩短。与对照组相比,PD模型组小鼠中脑黑质部位TH阳性神经元数目、TH蛋白表达减少,Th17组小鼠减少更明显。结论Th17细胞及其炎症因子可以加重PD小鼠的神经炎症反应。

Milk fat globule membrane supplementation protects againstβ-lactoglobul-ininduced food allergy in mice via upregulation of regulatory T cells and enhancement of intestinal barrier in a microbiota-derived short-chain fatty acids manner

Milk fat globule membrane(MFGM),which contains abundant glycoproteins and phospholipids,exerts beneficial effects on intestinal health and immunomodulation.The aim of this study was to evaluate the protective effects and possible underlying mechanisms of MFGM on cow’s milk allergy(CMA)in aβ-lactoglobulin(BLG)-induced allergic mice model.MFGM was supplemented to allergic mice induced by BLG at a dose of 400 mg/kg body weight.Results demonstrated that MFGM alleviated food allergy symptoms,decreased serum levels of lipopolysaccharide,pro-inflammatory cytokines,immunoglobulin(Ig)E,Ig G1,and Th2 cytokines including interleukin(IL)-4,while increased serum levels of Th1 cytokines including interferon-γand regulatory T cells(Tregs)cytokines including IL-10 and transforming growth factor-β.MFGM modulated gut microbiota and enhanced intestinal barrier of BLG-allergic mice,as evidenced by decreased relative abundance of Desulfobacterota,Rikenellaceae,Lachnospiraceae,and Desulfovibrionaceae,while increased relative abundance of Bacteroidetes,Lactobacillaceae and Muribaculaceae,and enhanced expressions of tight junction proteins including Occludin,Claudin-1 and zonula occludens-1.Furthermore,MFGM increased fecal short-chain fatty acids(SCFAs)levels,which elevated G protein-coupled receptor(GPR)43 and GPR109A expressions.The increased expressions of GPR43 and GPR109A induced CD103+dendritic cells accumulation and promoted Tregs differentiation in mesenteric lymph node to a certain extent.In summary,MFGM alleviated CMA in a BLG-induced allergic mice model through enhancing intestinal barrier and promoting Tregs differentiation,which may be correlated with SCFAs-mediated activation of GPRs.These findings suggest that MFGM may be useful as a promising functional ingredient against CMA.

Tumor-derived DEFB1 induces immune tolerance by inhibiting maturation of dendritic cell and impairing CD8+T cell function in esophageal squamous cell carcinoma

Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.

Comprehensive Understanding of Immune Cells in The Pathogenesis of Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease(NAFLD)is the most common chronic liver disease,defined by several phases,ranging from benign fat accumulation to non-alcoholic steatohepatitis(NASH),which can lead to liver cancer and cirrhosis.Although NAFLD is a disease of disordered metabolism,it also involves several immune cell-mediated inflammatory processes,either promoting and/or suppressing hepatocyte inflammation through the secretion of pro-inflammatory and/or anti-inflammatory factors to influence the NAFLD process.However,the underlying disease mechanism and the role of immune cells in NAFLD are still under investigation,leaving many open-ended questions.In this review,we presented the recent concepts about the interplay of immune cells in the onset and pathogenesis of NAFLD.We also highlighted the specific non-immune cells exhibiting immunological properties of therapeutic significance in NAFLD.We hope that this review will help guide the development of future NAFLD therapeutics.

Cellular strategies to induce immune tolerance after liver transplantation:Clinical perspectives

Liver transplantation(LT)has become the most efficient treatment for pediatric and adult end-stage liver disease and the survival time after transplantation is becoming longer due to the development of surgical techniques and perioperative management.However,long-term side-effects of immunosuppressants,like infection,metabolic disorders and malignant tumor are gaining more attention.Immune tolerance is the status in which LT recipients no longer need to take any immunosuppressants,but the liver function and intrahepatic histology maintain normal.The approaches to achieve immune tolerance after transplantation include spontaneous,operational and induced tolerance.The first two means require no specific intervention but withdrawing immunosuppressant gradually during follow-up.No clinical factors or biomarkers so far could accurately predict who are suitable for immunosuppressant withdraw after transplantation.With the understanding to the underlying mechanisms of immune tolerance,many strategies have been developed to induce tolerance in LT recipients.Cellular strategy is one of the most promising methods for immune tolerance induction,including chimerism induced by hematopoietic stem cells and adoptive transfer of regulatory immune cells.The safety and efficacy of various cell products have been evaluated by prospective preclinical and clinical trials,while obstacles still exist before translating into clinical practice.Here,we will summarize the latest perspectives and concerns on the clinical application of cellular strategies in LT recipients.

Immunomodulation of adipose-derived mesenchymal stem cells on peripheral blood mononuclear cells in colorectal cancer patients with COVID-19

BACKGROUND Accumulating evidence has shown that adipose tissue-derived mesenchymal stem cells(ADSCs)are an effective therapeutic approach for managing coronavirus disease 2019(COVID-19);however,further elucidation is required to determine their underlying immunomodulatory effect on the mRNA expression of T helper cell-related transcription factors(TFs)and cytokine release in peripheral blood mononuclear cells(PBMCs).AIM To investigate the impact of ADSCs on the mRNA expression of TFs and cytokine release in PBMCs from colorectal cancer(CRC)patients with severe COVID-19(CRC^(+)patients).METHODS PBMCs from CRC^(+)patients(PBMCs-C+)and age-matched CRC patients(PBMCs-C)were stimulated and cultured in the presence/absence of ADSCs.The mRNA levels of T-box TF TBX21(T-bet),GATA binding protein 3(GATA-3),RAR-related orphan receptor C(RORC),and forkhead box P3(FoxP3)in the PBMCs were determined by reverse transcriptase-polymerase chain reaction.Culture supernatants were evaluated for levels of interferon gamma(IFN-γ),interleukin 4(IL-4),IL-17A,and transforming growth factor beta 1(TGF-β1)using an enzyme-linked immunosorbent assay.RESULTS Compared with PBMCs-C,PBMCs-C+exhibited higher mRNA levels of T-bet and RORC,and increased levels of IFN-γ and IL-17A.Additionally,a significant decrease in FoxP3 mRNA and TGF-β1,as well as an increase in Tbet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios were observed in PBMCs-C+.Furthermore,ADSCs significantly induced a functional regulatory T cell(Treg)subset,as evidenced by an increase in FoxP3 mRNA and TGF-β1 release levels.This was accompanied by a significant decrease in the mRNA levels of T-bet and RORC,release of IFN-γ and IL-17A,and T-bet/GATA-3,RORC/FoxP3,IFN-γ/IL-4,and IL-17A/TGF-β1 ratios,compared with the PBMCs-C+alone.CONCLUSION The present in vitro studies showed that ADSCs contributed to the immunosuppressive effects on PBMCs-C+,favoring Treg responses.Thus,ADSC-based cell therapy could be a beneficial approach for patients with severe COVID-19 who fail to respond to conventional therapies.

Full T-cell activation and function in teleosts require collaboration of first and co-stimulatory signals

Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal.However,whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown.In the present study,we discovered that the Nile tilapia(Oreochromis niloticus)encodes key components of the LAT signalosome,namely,LAT,ITK,GRB2,VAV1,SLP-76,GADS,and PLC-γ1.These components are evolutionarily conserved,and CD3εmAb-induced T-cell activation markedly increased their expression.Additionally,at least ITK,GRB2,and VAV1 were found to interact with LAT for signalosome formation.Downstream of the first signal,the NF-κB,MAPK/ERK,and PI3K-AKT pathways were activated upon CD3εmAb stimulation.Furthermore,treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal.Combined CD3εand CD28 mAb stimulation enhanced ERK1/2 and S6 phosphorylation and elevated NFAT1,c-Fos,IL-2,CD122,and CD44 expression,thereby signifying T-cell activation.Moreover,rather than relying on the first or co-stimulatory signal alone,both signals were required for T-cell proliferation.Full T-cell activation was accompanied by marked apoptosis and cytotoxic responses.These findings suggest that tilapia relies on dual signaling to maintain an optimal T-cell response,providing a novel perspective for understanding the evolution of the adaptive immune system.

Impact of nanoparticles on immune cells and their potential applications in cancer immunotherapy

Nanoparticles represent a heterogeneous collection of materials,whether natural or synthetic,with dimensions aligning in the nanoscale.Because of their intense manifestation with the immune system,they can be harvested for numerous bio-medical and biotechnological advancements mainly in cancer treatment.This review article aims to scrutinize various types of nanoparticles that interact differently with immune cells like macrophages,dendritic cells,T lymphocytes,and natural killer(NK)cells.It also underscores the importance of knowing how nanoparticles influence immune cell functions,such as the production of cytokines and the presentation of antigens which are crucial for effective cancer immunotherapy.Hence overviews of bio-molecular mechanisms are provided.Nanoparticles can improve antigen presentation,boost T-cell responses,and overcome the immunosuppressive tumor environment.The regulatory mechanisms,signaling pathways,and nanoparticle characteristics are also presented for a comprehensive understanding.We review the nanotechnology platform options and challenges in nanoparticlesbased immunotherapy,from an immunotherapy perspective including precise targeting,immune modulation,and potential toxicity,as well as personalized approaches based on individual patient and tumor characteristics.The development of emerging multifunctional nanoparticles and theranostic nanoparticles will provide new solutions for the precision and efficiency of cancer therapies in next-generation practice.

Predicting the Prognosis and Immunotherapeutic Response of Triple-Negative Breast Cancer by Constructing a Prognostic Model Based on CD8+T Cell-Related Immune Genes

Objective Triple-negative breast cancer(TNBC)poses a significant challenge for treatment efficacy.CD8+T cells,which are pivotal immune cells,can be effectively analyzed for differential gene expression across diverse cell populations owing to rapid advancements in sequencing technology.By leveraging these genes,our objective was to develop a prognostic model that accurately predicts the prognosis of patients with TNBC and their responsiveness to immunotherapy.Methods Sample information and clinical data of TNBC were sourced from The Cancer Genome Atlas and METABRIC databases.In the initial stage,we identified 67 differentially expressed genes associated with immune response in CD8+T cells.Subsequently,we narrowed our focus to three key genes,namely CXCL13,GBP2,and GZMB,which were used to construct a prognostic model.The accuracy of the model was assessed using the validation set data and receiver operating characteristic(ROC)curves.Furthermore,we employed various methods,including Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway,immune infiltration,and correlation analyses with CD274(PD-L1)to explore the model's predictive efficacy in immunotherapeutic responses.Additionally,we investigated the potential underlying biological pathways that contribute to divergent treatment responses.Results We successfully developed a model capable of predicting the prognosis of patients with TNBC.The areas under the curve(AUC)values for the 1-,3-,and 5-year survival predictions were 0.618,0.652,and 0.826,respectively.Employing this risk model,we stratified the samples into high-and low-risk groups.Through KEGG enrichment analysis,we observed that the high-risk group predominantly exhibited enrichment in metabolism-related pathways such as drug and chlorophyll metabolism,whereas the low-risk group demonstrated significant enrichment in cytokine pathways.Furthermore,immune landscape analysis revealed noteworthy variations between(PD-L1)expression and risk scores,indicating that our model effectively predicted the response of patients to immune-based treatments.Conclusion Our study demonstrates the potential of CXCL13,GBP2,and GZMB as prognostic indicators of clinical outcomes and immunotherapy responses in patients with TNBC.These findings provide valuable insights and novel avenues for developing immunotherapeutic approaches targeting TNBC.

Regulatory T cells in skin regeneration and wound healing

As the body’s integumentary system,the skin is vulnerable to injuries.The subsequent wound healing processes aim to restore dermal and epidermal integrity and functionality.To this end,multiple tissue-resident cells and recruited immune cells cooperate to efficiently repair the injured tissue.Such temporally-and spatially-coordinated interplay necessitates tight regulation to prevent collateral damage such as overshooting immune responses and excessive inflammation.In this context,regulatory T cells(Tregs)hold a key role in balancing immune homeostasis and mediating cutaneous wound healing.A comprehensive understanding of Tregs’multifaceted field of activity may help decipher wound pathologies and,ultimately,establish new treatment modalities.Herein,we review the role of Tregs in orchestrating the regeneration of skin adnexa and catalyzing healthy wound repair.Further,we discuss how Tregs operate during fibrosis,keloidosis,and scarring.

DA大鼠骨髓来源PD-L1^(hi)tol-DC构建及其免疫学功能鉴定

目的构建DA大鼠骨髓来源程序性细胞死亡蛋白配体1(PD-LI)hi耐受性树突状细胞(tol-DC)并鉴定其免疫学功能。方法提取DA大鼠骨髓细胞,联合应用重组小鼠粒细胞巨噬细胞集落刺激因子和重组小鼠白细胞介素(IL)-4,体外培养6 d诱导骨髓细胞分化为未成熟树突状细胞(imDC);应用脂多糖刺激细胞成熟,继续培养2 d收集成熟树突状细胞(mDC);加入PD-L1慢病毒载体病毒原液或同等剂量慢病毒病毒原液,培养2 d后收集PD-L1^(hi)tol-DC和Lv-imDC。应用倒置相差显微镜及透射电镜观察PD-L1^(hi)tol-DC形态;实时荧光定量逆转录聚合酶链反应、蛋白质印迹法及流式细胞术检测细胞表面特异性标志物表达水平。将imDC、mDC、Lv-imDC及PD-L1^(hi)tol-DC分别与Lewis大鼠脾脏来源CD8^(+)T细胞共培养,酶联免疫吸附试验检测各组上清液炎症因子水平,流式细胞术分析各组T细胞凋亡及调节性T细胞(Treg)分化情况。结果经PD-L1基因修饰构建的PD-L1^(hi)tol-DC形态符合tol-DC特征,表面CD80、CD86、主要组织相容性复合体(MHC)表达水平较低。与CD8^(+)T细胞混合培养后,PD-L1^(hi)tol-DC组上清液IL-10、转化生长因子(TGF)-β1水平较高,肿瘤坏死因子(TNF)-α、IL-17A水平较低,T细胞凋亡及Treg分化增多。结论通过慢病毒载体过表达PD-L1可成功诱导构建DA大鼠骨髓来源PD-L1^(hi)tol-DC,促进抑炎因子分泌及T细胞凋亡,诱导Treg分化,抑制同种异体CD8^(+)T细胞免疫反应,这为下一步器官移植免疫耐受研究提供了实验依据。