BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechan...BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T(mTreg)cells functional levels.METHODS Following induction of the AIH mouse model induced by Concanavalin A(Con A),prophylactic administration of PTH was given for 10 d.The levels of mTreg cells were measured by flow cytometry,and intestinal microbiota was analyzed by 16S rRNA analysis,while western blotting was used to identify activation of the toll-like receptor(TLR)2,TLR4/nuclear factor-κB(NF-κB),and CXCL16/CXCR6 signaling pathways.RESULTS In the liver of mice with AIH,PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ,tumor necrosis factor-alpha,interleukin(IL)-1β,IL-2,IL-6,and IL-21 expression.Simultaneously,PTH stimulated the abundance of helpful bacteria,promoted activation of the TLR2 signal,which may enhance Treg/mTreg cells quantity to produce IL-10,and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways.CONCLUSION PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH,which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.展开更多
Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparamet...Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization.In case of chronic viral diseases such as human immunodeficiency virus-1,CD4+T_(SCM) cells,serve as major reservoirs of the latent virus.However,during immune activation and functional exhaustion of effector T cells,these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection.More recently,these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion.Similarly,studies are also investigating their pathological role in driving autoimmune responses.However,there are several gaps in the understanding of the role of T_(SCM) cells in viral and autoimmune diseases to make them potential therapeutic targets.In this minireview,we have attempted an updated compilation of the dyadic role of these complex T_(SCM) cells during such human diseases along with their biology and transcriptional programs.展开更多
Infections in infants and children under five years of age are a public health in México and are one of the major causes of death. Methods In this study, lymphocyte immunophenotyping for CD3+ (T-cells), CD3+CD4+,...Infections in infants and children under five years of age are a public health in México and are one of the major causes of death. Methods In this study, lymphocyte immunophenotyping for CD3+ (T-cells), CD3+CD4+, CD3+CD8+, CD3+CD19+, CD3+CD16/56+, CD45RA+, CD45RO+, CD62L- and CD28- were determined in the whole blood of gastrointestinal and respiratory bacterial infected children, using a four-color flow cytometry technique. Results: Our data showed that the percentages and the absolute numbers of monocytes and granulocytes are increased in infected children, when compared to the control group. Similarly, we observed increases in the percentages of B lymphocytes, CD8+ cells, memory T cells (CD4+CD45RO+ and CD8+CD45RO+) and effector lymphocytes (CD4+CD62L? and CD8+CD28?) in infected children compared with the control group. In contrast, naive T cells were decreased in the bacterial infected children relative to the control group. Additionally, we used ELISA assays to identify the pathogen agent in gastrointestinal and respiratory infection. Comparing different types of infection, we found that the children with respiratory bacterial infections had higher percentages of B lymphocytes, and cytotoxic lymphocytes (CD8+CD28-);and the children with gastrointestinal infections had higher percentages of CD3+ lymphocytes and effector cells (CD4+CD62L-). Conclusions The increase in B lymphocytes and CD8+CD28- cells in the children with respiratory infections and the increase of T lymphocytes and CD4+CD62L- cells in the children with gastrointestinal bacterial infections indicate that both cellular and humoral responses coincide, and both responses are necessary for eliminating the pathogen.展开更多
Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear c...Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma(RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival.Methods: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha.Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B(NF-КB)pathway.Results: RCC patients had a similar percentage of CD4^+ and CD8^+ Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved.Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway.Conclusions: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.展开更多
BACKGROUND Tissue resident memory T(TRM)cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.AIM To compare the efficacy and safety of the intralesional injection of 5-...BACKGROUND Tissue resident memory T(TRM)cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil(5-FU)and triamcinolone(TA)with those associated with TA alone for the treatment of chronic eczema.METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only.Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes.All patients were followed up monthly for up to 1 year.RESULTS No serious adverse event was observed in either group.Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment,the relapse rate was significantly lower in the 5-FU+TA group than in the TA group.Histological examination showed significantly fewer CD8^(+)and CD103^(+)T cells but not CD4^(+)T cells in the 5-FU+TA group.CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of T_(RM) cells in the lesional skin and the relapse rate of chronic eczema.展开更多
BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the ...BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ T_(RM) may play a role in the immunogenicity in MSI-H CRC(BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of T_(RM) cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.展开更多
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The patholog...Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.展开更多
Effective vaccination in duces memory T cells,which protect the host against pathogen re-infecti ons.Therefore,detection of memory T cells is essential for evaluating vaccine efficacy,which was originally dependent on...Effective vaccination in duces memory T cells,which protect the host against pathogen re-infecti ons.Therefore,detection of memory T cells is essential for evaluating vaccine efficacy,which was originally dependent on cytokine induction assays.Currently,two isoforms of CD45 tyrosine phosphatase,CD45RO expression and CD45RA exclusion(CD45RO^(+)/CD45RA^(-)) are used extensively for detecting memory T cells in cattle.The CD45RO^(+)/CD45RA^(-) markers were first established in humans around three decades ago,and were adopted in cattle soon after.However,in the last two decades,some published data in humans have challenged the initial paradigm,and required multiple markers for identifying memoryT cells.On the contrary,memoryT cell detection in cattle still mostly relies on CD45RO^(+)/CD45RA^(-)despite some con troversial evidence.In this review,we summarized the current literature to exami ne if CD45RO^(+)/CD45RA^(-)are valid markers for detecting memoryT cells in cattle.It seems CD45RA and CD45RO(CD45RA/RO)as markers for identifyi ng bovine memoryT cells are questi on able.展开更多
To investigate the role of CD4 + helper T (Th) cells in the memory CTL-mediated anti-tumor immunity, the RAG-1 gene knock out mice were adoptively transferred with OT-1 cells to generate the memory CTL, the C57BL/6 mi...To investigate the role of CD4 + helper T (Th) cells in the memory CTL-mediated anti-tumor immunity, the RAG-1 gene knock out mice were adoptively transferred with OT-1 cells to generate the memory CTL, the C57BL/6 mice immunized with the epitope peptide of OVA specific Th cells and with different adjuvants were adoptively transferred with these memory-CTLs, and then the animals were challenged with tumor cells EG7. It was found that although the simple immunization of mice with the epitope peptide of the OVA specific Th cells could generate more effect CTL, but this effect was not so strong enough to resist completely the challenges with tumor cells. Nevertheless, the memory CTL-mediated anti-tumor immune effect required the helps of Th1 and Th2 cells. The cross-regulation between Th1 and Th2 cells seemed to be beneficial for the host to generate more effector CTL for mounting an efficient anti-tumor response. It concluded that the interaction between Th1 and Th2 cells might be more important than the single subset of Th cells in the memory CTL-mediated anti-tumor immune response. More attention should be paid in this regard for the future studies.展开更多
Objective To investigate the role of OX40 in the mechanisms of memory T cells in islet transplant tolerance. Methods The expression of OX40 on native, like memory and memory CD8 + T cells was detected by RT - PCR. Spl...Objective To investigate the role of OX40 in the mechanisms of memory T cells in islet transplant tolerance. Methods The expression of OX40 on native, like memory and memory CD8 + T cells was detected by RT - PCR. Splenic T ceels from B6 mice were injected into Rag - / - mice via the tail vein,and the Rag mice were divided into three groups ( n = 8 each) :展开更多
目的以雌性和雄性非肥胖糖尿病(nonobese diabetic,NOD)小鼠以及健康对照癌症研究所(institute for cancer research,ICR)小鼠为研究对象,比较分析初始、效应、记忆、耗竭以及调节性CD8^(+)T细胞分化亚群差异,探讨1型糖尿病(type 1 diab...目的以雌性和雄性非肥胖糖尿病(nonobese diabetic,NOD)小鼠以及健康对照癌症研究所(institute for cancer research,ICR)小鼠为研究对象,比较分析初始、效应、记忆、耗竭以及调节性CD8^(+)T细胞分化亚群差异,探讨1型糖尿病(type 1 diabetes,T1D)背景下的性别因素对CD8^(+)T细胞分化命运的影响。方法采用流式细胞术检测雌雄NOD小鼠脾脏、胰腺引流淋巴结(pancreatic draining lymph nodes,pLN)、胰腺浸润淋巴细胞(pancreas-infiltrating lymphocytes,PIL)、初始T细胞(naive T cells,T_(N))、中枢记忆T细胞(central memory T cells,T_(CM))、效应T细胞(effector T cells,T_(EFF))、效应前体样T细胞(effector precursor T cells,T_(EP))、耗竭T细胞(exhausted T cells,T_(EX))、耗竭前体T细胞(precursor exhausted T cells,T_(PEX))以及调节性T细胞(regulatory T cells,Tregs)等CD8^(+)T细胞分化亚群的频率和表型差异。结果与雄性NOD小鼠比较,雌性NOD小鼠pLN及PIL中IFN-γ^(+)、CD107a^(+)和CCL5^(+)CD8^(+)T_(EFF)频率显著升高(P<0.01,P<0.05,P<0.05),同时脾脏中CD8^(+)T_(N)、CD8^(+)T_(CM)、CD8^(+)T_(EX)、CD8^(+)T_(PEX)和CD122^(+)CD8^(+)Tregs亚群的频率均显著降低(P<0.01,P<0.01,P<0.01,P<0.01,P<0.001);而雌性和雄性ICR小鼠体内除CD122^(+)CD8^(+)Tregs差异变化与NOD小鼠一致(P<0.05),其余上述各CD8^(+)T细胞分化亚群无显著差异。结论雄激素可能通过抑制记忆T细胞向效应T细胞分化,同时促进效应T细胞功能耗竭,导致雌雄发病率差异。展开更多
BACKGROUND:Patients with sepsis often exhibit an acute inflammatory response,followed by an immunosuppressive phase with a poor immune response.However,the underlying mechanisms have not been fully elucidated.METHODS:...BACKGROUND:Patients with sepsis often exhibit an acute inflammatory response,followed by an immunosuppressive phase with a poor immune response.However,the underlying mechanisms have not been fully elucidated.METHODS:We sought to comprehensively characterize the transcriptional changes in neutrophils of patients with sepsis by transcriptome sequencing.Additionally,we conducted a series of experiments,including real-time quantitative polymerase chain reaction(RT-qPCR)and flow cytometry to investigate the role of arginase-1 signaling in sepsis.RESULTS:Through the analysis of gene expression profiles,we identified that the negative regulation of T cell activation signaling was enriched,and the expression of arginase-1 was high in neutrophils from patients with sepsis.Furthermore,we conducted flow cytometry and found that the function of CD8^(+)T cells in septic patients was impaired.Moreover,neutrophils from septic patients inhibited the percentage of polyfunctional effector CD8^(+)T cells through arginase-1.Additionally,the proportions of granzyme B^(+)IFN^(-)γ^(+)CD8^(+)T and TNF^(-)α^(+)IFN^(-)γ^(+)CD8^(+)T cells increased after inhibition of arginase-1 signaling.CONCLUSION:The impaired effector function of CD8^(+)T cells could be restored by blocking arginase-1 signaling in patients with sepsis.展开更多
Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specifi...Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specific CD8+ T cells play an important role in the course and outcome of these viral infections and it is hypothesized that altered or impaired differentiation of virus- specific CD8+ T cells contributes to the development of persistence and/or disease progression. A deeper understanding of the mechanisms responsible for functional differentiation of CD8+ T cells is essential for the generation of successful therapies aiming to strengthen the adaptive component of the immune system.展开更多
When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that ar...When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.展开更多
目的探讨吉兰-巴雷综合征(Guillain-Barrésyndrome,GBS)患者外周血记忆性T细胞和记忆性B细胞亚群的变化及其临床意义。方法选取2018年6月至2020年12月于徐州医科大学附属医院神经内科住院的16例GBS患者作为研究组,并选取同期16名...目的探讨吉兰-巴雷综合征(Guillain-Barrésyndrome,GBS)患者外周血记忆性T细胞和记忆性B细胞亚群的变化及其临床意义。方法选取2018年6月至2020年12月于徐州医科大学附属医院神经内科住院的16例GBS患者作为研究组,并选取同期16名来院的健康体检者作为对照组。流式细胞术检测两组入选者的外周血T细胞亚群,包括CD4^(+)初始T细胞(naive T cells,TN)、CD4^(+)中央记忆性T细胞(central memory T cells,TCM)、CD4^(+)效应记忆性T细胞(effector memory T cells,TEM)和CD4^(+)终末分化效应记忆性T细胞(terminally differentiated effector memory T cells,TEMRA)及记忆性B细胞、浆母细胞的占比并分析其临床价值。结果与对照组相比,研究组患者的CD4^(+)TN及CD8^(+)TN均明显下降(P<0.05),CD4^(+)TEM及CD8^(+)TEM均明显升高(P<0.05),TCM及TEMRA在CD4和CD8上的比例比较,差异无统计学意义(P>0.05)。与对照组相比,研究组记忆性B细胞比例明显升高(P<0.05),两组患者间浆母细胞占比比较,差异无统计学意义(P>0.05)。GBS患者外周血CD4^(+)TEM及CD8^(+)TEM占比与Hughes残疾评分、脑脊液蛋白、脑脊液免疫球蛋白G及记忆性B细胞占比均呈正相关(P<0.05)。结论GBS患者存在记忆性T细胞和记忆性B细胞亚群免疫紊乱,CD4^(+)TEM细胞、CD8^(+)TEM细胞及记忆性B细胞占比升高,这很可能是GBS发病过程中重要的外周免疫机制。展开更多
Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, th...Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, the extent to which specific memory phenotypic categories of CD8+ T cells reliably represent their functional attributes remains controversial. Methods: We simultaneously assessed surface phenotype and functionality of HIV-specific CD8+ T cells by multiparametric flow cytometry, measuring five CD8+ T cell functions (CD107a, IFNγ, MIP-1β, TNFα and IL2) and phenotypic markers CCR7, CD45RA, and CD27, in parallel in 24 HIV-infected individuals. Results: Virus-specific responses were contained within all eight phenotypic categories defined using CCR7, CD45RA, and CD27. Phenotypic profiles of HIV-specific cells differed from CEF-specific cells, with HIV-specific cells having higher levels of CD45RA (p = 0.008). Interestingly a large portion of CEF and HIV-specific cells were found within previously undefined phenotypes CCR7+CD27-CD45RA+ (14.6% and 17.2%, respectively) and CCR7+CD27-CD45RA-(14.8% and 15.8%, respectively). In addition, up to 10% - 20% of responding cells were phenotypically “naive”. Additionally, memory phenotypes of cells exhibiting monofunctional and polyfunctional responses frequently differed, and failed to associate with a consistent phenotype representing functionally active cells. Conclusion: These data suggest that particularly after antigen stimulation, that surface phenotypes defined by CCR7, CD27 and CD45RA expression on antigen-specific CD8+ T cells, reflect a wide range of immunological functions, and that no single phenotype defined by memory marker expression can reliably be used to identify functional capacity.展开更多
基金Supported by the National Natural Science Foundation of China,No.81603402,82060798,81860791the Special Fund Project for Graduate Innovation of Jiangxi University of Chinese Medicine,No.JZYC22S77+3 种基金a Special Fund Project for Graduate Innovation of Jiangxi Province,No.YC2022-s840,YC2022-B188Jiangxi University of Chinese Medicine Science and Technology Innovation Team Development Program,No.CXTD22008the Young and Middle-aged Backbone Talent Project of Jiangxi Administration of Traditional Chinese Medicine,No.[2020]05Young Qhuang Scholars support Project of National Administration of Traditional Chinese Medicine,No.[2022]256.
文摘BACKGROUND Traditional Chinese medicine has used the drug Pien Tze Huang(PTH),a classic prescription,to treat autoimmune hepatitis(AIH).However,the precise mode of action is still unknown.AIM To investigate the mechanism of PTH in an AIH mouse model by determining the changes in gut microbiota structure and memory regulatory T(mTreg)cells functional levels.METHODS Following induction of the AIH mouse model induced by Concanavalin A(Con A),prophylactic administration of PTH was given for 10 d.The levels of mTreg cells were measured by flow cytometry,and intestinal microbiota was analyzed by 16S rRNA analysis,while western blotting was used to identify activation of the toll-like receptor(TLR)2,TLR4/nuclear factor-κB(NF-κB),and CXCL16/CXCR6 signaling pathways.RESULTS In the liver of mice with AIH,PTH relieved the pathological damage and reduced the numbers of T helper type 17 cells and interferon-γ,tumor necrosis factor-alpha,interleukin(IL)-1β,IL-2,IL-6,and IL-21 expression.Simultaneously,PTH stimulated the abundance of helpful bacteria,promoted activation of the TLR2 signal,which may enhance Treg/mTreg cells quantity to produce IL-10,and suppressed activation of the TLR4/NF-κB and CXCL16/CXCR6 signaling pathways.CONCLUSION PTH regulates intestinal microbiota balance and restores mTreg cells to alleviate experimental AIH,which is closely related to the TLR/CXCL16/CXCR6/NF-κB signaling pathway.
文摘Stem cell-like memory T(TSCM)cells possess stem cell properties including multipotency and self-renewal and are being recognized as emerging players in various human diseases.Advanced technologies such as multiparametric flowcytometry and single cell sequencing have enabled their identification and molecular characterization.In case of chronic viral diseases such as human immunodeficiency virus-1,CD4+T_(SCM) cells,serve as major reservoirs of the latent virus.However,during immune activation and functional exhaustion of effector T cells,these cells also possess the potential to replenish the pool of functional effector cells to curtail the infection.More recently,these cells are speculated to play important role in protective immunity following acute viral infections such as coronavirus disease 2019 and might be amenable for therapeutics by ex vivo expansion.Similarly,studies are also investigating their pathological role in driving autoimmune responses.However,there are several gaps in the understanding of the role of T_(SCM) cells in viral and autoimmune diseases to make them potential therapeutic targets.In this minireview,we have attempted an updated compilation of the dyadic role of these complex T_(SCM) cells during such human diseases along with their biology and transcriptional programs.
文摘Infections in infants and children under five years of age are a public health in México and are one of the major causes of death. Methods In this study, lymphocyte immunophenotyping for CD3+ (T-cells), CD3+CD4+, CD3+CD8+, CD3+CD19+, CD3+CD16/56+, CD45RA+, CD45RO+, CD62L- and CD28- were determined in the whole blood of gastrointestinal and respiratory bacterial infected children, using a four-color flow cytometry technique. Results: Our data showed that the percentages and the absolute numbers of monocytes and granulocytes are increased in infected children, when compared to the control group. Similarly, we observed increases in the percentages of B lymphocytes, CD8+ cells, memory T cells (CD4+CD45RO+ and CD8+CD45RO+) and effector lymphocytes (CD4+CD62L? and CD8+CD28?) in infected children compared with the control group. In contrast, naive T cells were decreased in the bacterial infected children relative to the control group. Additionally, we used ELISA assays to identify the pathogen agent in gastrointestinal and respiratory infection. Comparing different types of infection, we found that the children with respiratory bacterial infections had higher percentages of B lymphocytes, and cytotoxic lymphocytes (CD8+CD28-);and the children with gastrointestinal infections had higher percentages of CD3+ lymphocytes and effector cells (CD4+CD62L-). Conclusions The increase in B lymphocytes and CD8+CD28- cells in the children with respiratory infections and the increase of T lymphocytes and CD4+CD62L- cells in the children with gastrointestinal bacterial infections indicate that both cellular and humoral responses coincide, and both responses are necessary for eliminating the pathogen.
基金supported by grants from the National Science and Technology Support Project (Grant No. 2015BAI12B12)the National Natural Science Foundation of China (Grant No. 81401887)+1 种基金the National Natural Science Foundation of China (Grant No. 81470293)the Tianjin Natural Science Foundation (Grant No. 14JCQNJC11500)
文摘Objective: Memory stem T cells(Tscm) have attracted attention because of their enhanced self-renewal, multipotent capacity, and anti-tumor capacities. However, little is known about Tscm in patients with renal clear cell carcinoma(RCC) and the role of Wnt signaling in these cells. We evaluated Tscm from RCC patients concerning their activation of Wnt signaling in vitro and explored the mechanism of preferential survival.Methods: Flow cytometry identified surface markers and cytokines produced from accumulated Tscm in the presence of the glycogen synthase kinase beta inhibitor TWS119. Apoptosis was evaluated after induction using tumor necrosis factor-alpha.Immunofluorescence and Western blot analyses were used to investigate the activation of the nuclear factor-kappa B(NF-КB)pathway.Results: RCC patients had a similar percentage of CD4^+ and CD8^+ Tscm as healthy donors. Activation of Wnt signaling by TWS119 resulted in the accumulation of Tscm in activated T cells, but reversal of differentiated T cells to Tscm was not achieved.Preferential survival of Tscm was associated with increased anti-apoptotic ability mediated downstream of the NF-КB activation pathway.Conclusions: The finding that Tscm can accumulate by Wnt signaling in vitro in blood from RCC patients will help in devising new cancer therapy strategies of Tscm-based adoptive immunotherapy, such as dendritic cell-stimulated Tscm, and T cell receptor or chimeric antigen receptor-engineered Tscm.
基金Pudong New District Science and Technology Development Fund People’s Livelihood Scientific Research Special Fund(No.PKJ2018-Y42)the Shanghai Pudong New District Health System Discipline Construction Project(No.PWZzk 2017-14)the School-level Scientific Research Project of Shanghai University of Medicine and Health Sciences Affiliated with Zhoupu Hospital(No.ZPXM-2019A-13).
文摘BACKGROUND Tissue resident memory T(TRM)cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil(5-FU)and triamcinolone(TA)with those associated with TA alone for the treatment of chronic eczema.METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only.Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes.All patients were followed up monthly for up to 1 year.RESULTS No serious adverse event was observed in either group.Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment,the relapse rate was significantly lower in the 5-FU+TA group than in the TA group.Histological examination showed significantly fewer CD8^(+)and CD103^(+)T cells but not CD4^(+)T cells in the 5-FU+TA group.CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of T_(RM) cells in the lesional skin and the relapse rate of chronic eczema.
文摘BACKGROUND Recent studies in non-colorectal malignancy have associated T resident memory(T_(RM)) cells with improved patient survival. It is unknown if T_(RM) plays a role in colorectal cancer(CRC).AIM To examine the potential role of T_(RM) cells in providing immunogenicity in CRC stratified by microsatellite instability(MSI) and BRAF status.METHODS Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry(IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera(Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in in Form 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.RESULTS Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ T_(RM) cells in the MSI(BRAF mutant and wild type) group over the microsatellite stable(MSS) group. There was a statistically significant difference in CD8+ T_(RM) between high level MSI(MSI-H):BRAF mutant [22.57, 95% confidence interval(CI): 14.31-30.84] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0076 and MSI-H:BRAF wild type [16.18(95%CI: 10.44-21.93)] vs MSS [8.031(95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells(both CD8+CD103-and CD8+CD103+T_(RM)) between MSI-H: BRAF mutant and wild type CRC.CONCLUSION This study has shown that CD8+ T_(RM) are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ T_(RM) may play a role in the immunogenicity in MSI-H CRC(BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of T_(RM) cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.
基金supported by the Helmholtz-Gemeinschaft,“Zukunft-sthema”Immunology and inflammation”(ZT-0027)supported by the Pertermax-Müller-Stiftung and the Niedersachsen Research Network on Neuroinfectiology(N-RENNT)of the Ministry of Science and Culture of Lower Saxony
文摘Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.
基金supported by USDA NIFA Grant 2016-67015-24948(to ZX)Grant 2019-67015-29831(to ZX)+1 种基金the Jorgensen Foundation(to ZX)MAES program in University of Maryland(to ZX).
文摘Effective vaccination in duces memory T cells,which protect the host against pathogen re-infecti ons.Therefore,detection of memory T cells is essential for evaluating vaccine efficacy,which was originally dependent on cytokine induction assays.Currently,two isoforms of CD45 tyrosine phosphatase,CD45RO expression and CD45RA exclusion(CD45RO^(+)/CD45RA^(-)) are used extensively for detecting memory T cells in cattle.The CD45RO^(+)/CD45RA^(-) markers were first established in humans around three decades ago,and were adopted in cattle soon after.However,in the last two decades,some published data in humans have challenged the initial paradigm,and required multiple markers for identifying memoryT cells.On the contrary,memoryT cell detection in cattle still mostly relies on CD45RO^(+)/CD45RA^(-)despite some con troversial evidence.In this review,we summarized the current literature to exami ne if CD45RO^(+)/CD45RA^(-)are valid markers for detecting memoryT cells in cattle.It seems CD45RA and CD45RO(CD45RA/RO)as markers for identifyi ng bovine memoryT cells are questi on able.
文摘To investigate the role of CD4 + helper T (Th) cells in the memory CTL-mediated anti-tumor immunity, the RAG-1 gene knock out mice were adoptively transferred with OT-1 cells to generate the memory CTL, the C57BL/6 mice immunized with the epitope peptide of OVA specific Th cells and with different adjuvants were adoptively transferred with these memory-CTLs, and then the animals were challenged with tumor cells EG7. It was found that although the simple immunization of mice with the epitope peptide of the OVA specific Th cells could generate more effect CTL, but this effect was not so strong enough to resist completely the challenges with tumor cells. Nevertheless, the memory CTL-mediated anti-tumor immune effect required the helps of Th1 and Th2 cells. The cross-regulation between Th1 and Th2 cells seemed to be beneficial for the host to generate more effector CTL for mounting an efficient anti-tumor response. It concluded that the interaction between Th1 and Th2 cells might be more important than the single subset of Th cells in the memory CTL-mediated anti-tumor immune response. More attention should be paid in this regard for the future studies.
文摘Objective To investigate the role of OX40 in the mechanisms of memory T cells in islet transplant tolerance. Methods The expression of OX40 on native, like memory and memory CD8 + T cells was detected by RT - PCR. Splenic T ceels from B6 mice were injected into Rag - / - mice via the tail vein,and the Rag mice were divided into three groups ( n = 8 each) :
文摘目的以雌性和雄性非肥胖糖尿病(nonobese diabetic,NOD)小鼠以及健康对照癌症研究所(institute for cancer research,ICR)小鼠为研究对象,比较分析初始、效应、记忆、耗竭以及调节性CD8^(+)T细胞分化亚群差异,探讨1型糖尿病(type 1 diabetes,T1D)背景下的性别因素对CD8^(+)T细胞分化命运的影响。方法采用流式细胞术检测雌雄NOD小鼠脾脏、胰腺引流淋巴结(pancreatic draining lymph nodes,pLN)、胰腺浸润淋巴细胞(pancreas-infiltrating lymphocytes,PIL)、初始T细胞(naive T cells,T_(N))、中枢记忆T细胞(central memory T cells,T_(CM))、效应T细胞(effector T cells,T_(EFF))、效应前体样T细胞(effector precursor T cells,T_(EP))、耗竭T细胞(exhausted T cells,T_(EX))、耗竭前体T细胞(precursor exhausted T cells,T_(PEX))以及调节性T细胞(regulatory T cells,Tregs)等CD8^(+)T细胞分化亚群的频率和表型差异。结果与雄性NOD小鼠比较,雌性NOD小鼠pLN及PIL中IFN-γ^(+)、CD107a^(+)和CCL5^(+)CD8^(+)T_(EFF)频率显著升高(P<0.01,P<0.05,P<0.05),同时脾脏中CD8^(+)T_(N)、CD8^(+)T_(CM)、CD8^(+)T_(EX)、CD8^(+)T_(PEX)和CD122^(+)CD8^(+)Tregs亚群的频率均显著降低(P<0.01,P<0.01,P<0.01,P<0.01,P<0.001);而雌性和雄性ICR小鼠体内除CD122^(+)CD8^(+)Tregs差异变化与NOD小鼠一致(P<0.05),其余上述各CD8^(+)T细胞分化亚群无显著差异。结论雄激素可能通过抑制记忆T细胞向效应T细胞分化,同时促进效应T细胞功能耗竭,导致雌雄发病率差异。
基金This work was supported by the Research Fund for the Key Laboratory of Anhui Province(KLICD-2022-Z2)the Scientific Research Fund of Anhui Medical University(2011×kj083)the Scientific Research Fund of the First People's Hospital of Hefei(201642).
文摘BACKGROUND:Patients with sepsis often exhibit an acute inflammatory response,followed by an immunosuppressive phase with a poor immune response.However,the underlying mechanisms have not been fully elucidated.METHODS:We sought to comprehensively characterize the transcriptional changes in neutrophils of patients with sepsis by transcriptome sequencing.Additionally,we conducted a series of experiments,including real-time quantitative polymerase chain reaction(RT-qPCR)and flow cytometry to investigate the role of arginase-1 signaling in sepsis.RESULTS:Through the analysis of gene expression profiles,we identified that the negative regulation of T cell activation signaling was enriched,and the expression of arginase-1 was high in neutrophils from patients with sepsis.Furthermore,we conducted flow cytometry and found that the function of CD8^(+)T cells in septic patients was impaired.Moreover,neutrophils from septic patients inhibited the percentage of polyfunctional effector CD8^(+)T cells through arginase-1.Additionally,the proportions of granzyme B^(+)IFN^(-)γ^(+)CD8^(+)T and TNF^(-)α^(+)IFN^(-)γ^(+)CD8^(+)T cells increased after inhibition of arginase-1 signaling.CONCLUSION:The impaired effector function of CD8^(+)T cells could be restored by blocking arginase-1 signaling in patients with sepsis.
基金NIH National Center for Research Resources K12 RR017643 and NIH K08 AI072191 (HR)the National Institutes of Health through the Grand Challenges in Global Health Initiative, Cancer Research Institute Investigator Award, Woodruff Health Sciences Fund, Yerkes Research Center Base Grant RR-00165 and NIH AI070101 (AG)
文摘Chronic viral infections such as hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are major global health problems affecting more than 500 million people worldwide. Virus-specific CD8+ T cells play an important role in the course and outcome of these viral infections and it is hypothesized that altered or impaired differentiation of virus- specific CD8+ T cells contributes to the development of persistence and/or disease progression. A deeper understanding of the mechanisms responsible for functional differentiation of CD8+ T cells is essential for the generation of successful therapies aiming to strengthen the adaptive component of the immune system.
基金Supported by a fellowship obt-ained by Nolt-e MA from t-he Landst-einer Foundat-ion for Blood Transfusion Research(www.lsbr.nl),No.#1014
文摘When hematopoietic stem and progenitor cells(HSPC)are harvested for transplantation, either from the bone marrow or from mobilized blood, the graft contains a significant number of T cells. It is these T cells that are the major drivers of graft-vs-host disease(Gv HD). The risk for Gv HD can simply be reduced by the removal of these T cells from the graft. However, this is not always desirable, as this procedure also decreases the engraftment of the transplanted HSPCs and, if applicable, a graft-vs-tumor effect. This poses an important conundrum in the field: T cells act as a double-edged sword upon allogeneic HSPC transplantation, as they support engraftment of HSPCs and provide anti-tumor activity, but can also cause Gv HD. It has recently been suggested that T cells also enhance the engraftment of autologous HSPCs, thus supporting the notion that T cells and HSPCs have an important functional interaction that is highly beneficial, in particular during transplantation. The underlying reason on why and how T cells contribute to HSPC engraftment is still poorly understood. Therefore, we evaluate in this review the studies that have examined the role of T cells during HSPC transplantation and the possible mechanisms involved in their supporting function. Understanding the underlying cellular and molecular mechanisms can provide new insight into improving HSPC engraftment and thus lower the number of HSPCs required during transplantation. Moreover, it could provide new avenues to limit the development of severe Gv HD, thus making HSPC transplantations more efficient and ultimately safer.
文摘目的探讨吉兰-巴雷综合征(Guillain-Barrésyndrome,GBS)患者外周血记忆性T细胞和记忆性B细胞亚群的变化及其临床意义。方法选取2018年6月至2020年12月于徐州医科大学附属医院神经内科住院的16例GBS患者作为研究组,并选取同期16名来院的健康体检者作为对照组。流式细胞术检测两组入选者的外周血T细胞亚群,包括CD4^(+)初始T细胞(naive T cells,TN)、CD4^(+)中央记忆性T细胞(central memory T cells,TCM)、CD4^(+)效应记忆性T细胞(effector memory T cells,TEM)和CD4^(+)终末分化效应记忆性T细胞(terminally differentiated effector memory T cells,TEMRA)及记忆性B细胞、浆母细胞的占比并分析其临床价值。结果与对照组相比,研究组患者的CD4^(+)TN及CD8^(+)TN均明显下降(P<0.05),CD4^(+)TEM及CD8^(+)TEM均明显升高(P<0.05),TCM及TEMRA在CD4和CD8上的比例比较,差异无统计学意义(P>0.05)。与对照组相比,研究组记忆性B细胞比例明显升高(P<0.05),两组患者间浆母细胞占比比较,差异无统计学意义(P>0.05)。GBS患者外周血CD4^(+)TEM及CD8^(+)TEM占比与Hughes残疾评分、脑脊液蛋白、脑脊液免疫球蛋白G及记忆性B细胞占比均呈正相关(P<0.05)。结论GBS患者存在记忆性T细胞和记忆性B细胞亚群免疫紊乱,CD4^(+)TEM细胞、CD8^(+)TEM细胞及记忆性B细胞占比升高,这很可能是GBS发病过程中重要的外周免疫机制。
文摘Objectives: The definition of CD8+ T cell attributes that mediate protective immunity in HIV dis-ease progression has not been clearly defined. Although our ability to characterize these cells continues to improve, the extent to which specific memory phenotypic categories of CD8+ T cells reliably represent their functional attributes remains controversial. Methods: We simultaneously assessed surface phenotype and functionality of HIV-specific CD8+ T cells by multiparametric flow cytometry, measuring five CD8+ T cell functions (CD107a, IFNγ, MIP-1β, TNFα and IL2) and phenotypic markers CCR7, CD45RA, and CD27, in parallel in 24 HIV-infected individuals. Results: Virus-specific responses were contained within all eight phenotypic categories defined using CCR7, CD45RA, and CD27. Phenotypic profiles of HIV-specific cells differed from CEF-specific cells, with HIV-specific cells having higher levels of CD45RA (p = 0.008). Interestingly a large portion of CEF and HIV-specific cells were found within previously undefined phenotypes CCR7+CD27-CD45RA+ (14.6% and 17.2%, respectively) and CCR7+CD27-CD45RA-(14.8% and 15.8%, respectively). In addition, up to 10% - 20% of responding cells were phenotypically “naive”. Additionally, memory phenotypes of cells exhibiting monofunctional and polyfunctional responses frequently differed, and failed to associate with a consistent phenotype representing functionally active cells. Conclusion: These data suggest that particularly after antigen stimulation, that surface phenotypes defined by CCR7, CD27 and CD45RA expression on antigen-specific CD8+ T cells, reflect a wide range of immunological functions, and that no single phenotype defined by memory marker expression can reliably be used to identify functional capacity.