共查询到20条相似文献,搜索用时 31 毫秒
1.
Y. Tanaka I. Matsumoto A. Inoue N. Umeda C. Takai T. Sumida 《Clinical and experimental immunology》2014,177(2):419-427
Human cartilage gp‐39 (HC gp‐39) is a well‐known autoantigen in rheumatoid arthritis (RA). However, the exact localization, fluctuation and function of HC gp‐39 in RA are unknown. Therefore, using a glucose‐6‐phosphate isomerase (GPI)‐induced model of arthritis, we investigated these aspects of HC gp‐39 in arthritis. The rise in serum HC gp‐39 levels was detected on the early phase of GPI‐induced arthritis (day 7) and the HC gp‐39 mRNA was increased significantly on splenic CD4+T cells on day7, but not on CD11b+cells. Moreover, to identify the characterization of HC gp‐39+CD4+T cells, we assessed the analysis of T helper (Th) subsets. As a result, HC gp‐39 was expressed dominantly in CD4+CD25+ forkhead box protein 3 (FoxP3)+ refulatory T cells (Treg), but not in Th1, Th2 or Th17 cells. Furthermore, to investigate the effect of HC gp‐39 to CD4+T cells, T cell proliferation assay and cytokine production from CD4+T cells using recombinant HC gp‐39 was assessed. We found that GPI‐specific T cell proliferation and interferon (IFN)‐γ or interleukin (IL)‐17 production were clearly suppressed by addition of recombinant HC gp‐39. Antigen‐specific over‐expression of HC gp‐39 in splenic CD4+CD25+ FoxP3+ Treg cells occurs in the induction phase of GPI‐induced arthritis, and addition of recombinant HC gp‐39 suppresses antigen‐specific T‐cell proliferation and cytokine production, suggesting that HC gp‐39 in CD4+ T cells might play a regulatory role in arthritis. 相似文献
2.
CD4+ T cell anergy reflects the inability of CD4+ T cells to respond functionally to antigenic stimulation through proliferation or IL‐2 secretion. Histone deacetylase (HDAC) inhibitors have been shown to induce anergy in antigen‐activated CD4+ T cells. However, questions remain if HDAC inhibitors mediate anergy through direct action upon activated CD4+ T cells or through the generation and/or enhancement of regulatory T (Treg) cells. To assess if HDAC inhibitor n‐butyrate induces anergy independent of the generation or expansion of FoxP3+ Treg cells in vitro, we examine n‐butyrate‐treated murine CD4+ T cells for anergy induction and FoxP3+ Treg activity. Whereas n‐butyrate decreases CD4+ T cell proliferation and IL‐2 secretion, n‐butyrate did not augment FoxP3 protein production or confer a suppressive phenotype upon CD4+ T cells. Collectively, these data suggest that HDAC inhibitors can facilitate CD4+ T cell functional unresponsiveness directly and independently of Treg cell involvement. 相似文献
3.
T‐bet regulates differentiation of forkhead box protein 3+ regulatory T cells in programmed cell death‐1‐deficient mice
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
M. Tahara Y. Kondo M. Yokosawa H. Tsuboi S. Takahashi S. Shibayama I. Matsumoto T. Sumida 《Clinical and experimental immunology》2015,179(2):197-209
Programmed cell death‐1 (PD‐1) plays an important role in peripheral T cell tolerance, but whether or not it affects the differentiation of helper T cell subsets remains elusive. Here we describe the importance of PD‐1 in the control of T helper type 1 (Th1) cell activation and development of forkhead box protein 3 (FoxP3+) regulatory T cells (Tregs). PD‐1‐deficient T cell‐specific T‐bet transgenic (P/T) mice showed growth retardation, and the majority died within 10 weeks. P/T mice showed T‐bet over‐expression, increased interferon (IFN)‐γ production by CD4+ T cells and significantly low FoxP3+ Treg cell percentage. P/T mice developed systemic inflammation, which was probably induced by augmented Th1 response and low FoxP3+ Treg count. The study identified a unique, previously undescribed role for PD‐1 in Th1 and Treg differentiation, with potential implication in the development of Th1 cell‐targeted therapy. 相似文献
4.
S. M. Toor A. S. Syed Khaja I. Alkurd E. Elkord 《Clinical and experimental immunology》2018,191(2):189-197
Programmed death‐1 (PD‐1) and interactions with PD‐ligand 1 (PD‐L1) play critical roles in the tumour evasion of immune responses through different mechanisms, including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumour‐infiltrating T cells and regulatory T cell (Treg) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti‐PD‐1 antibody, pembrolizumab, on various Treg subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD‐1 expression in both cohorts. We found that PD‐1 was expressed mainly on CD4+CD25+ T cells and pembrolizumab had a greater effect on PD‐1 expression in CD4+CD25? T cells, compared to CD4+CD25+ cells. In addition, pembrolizumab did not affect the expression levels of Treg‐related markers, including cytotoxic T lymphocyte antigen‐4 (CTLA‐4), CD15s, latency‐associated peptide (LAP) and Ki‐67. Moreover, we report that CD15s is expressed mainly on forkhead box P3 (FoxP3)?Helios+ Treg in HD, but it is expressed on FoxP3+Helios? Treg subset in addition to FoxP3?Helios+ Treg in PBC. Pembrolizumab did not affect the levels of FoxP3+/?Helios+/? Treg subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect Treg or change their phenotype or function but rather blocks signalling via the PD‐1/PD‐L1 axis in activated T cells. 相似文献
5.
A. U. Engela M. J. Hoogduijn K. Boer N. H. R. Litjens M. G. H. Betjes W. Weimar C. C. Baan 《Clinical and experimental immunology》2013,173(2):343-354
Due to their immunomodulatory properties, mesenchymal stem cells (MSC) are interesting candidates for cellular therapy for autoimmune disorders, graft‐versus‐host disease and allograft rejection. MSC inhibit the proliferation of effector T cells and induce T cells with a regulatory phenotype. So far it is unknown whether human MSC‐induced CD4+CD25+CD127–forkhead box P3 (FoxP3)+ T cells are functional and whether they originate from effector T cells or represent expanded natural regulatory T cells (nTreg). Perirenal adipose‐tissue derived MSC (ASC) obtained from kidney donors induced a 2·1‐fold increase in the percentage of CD25+CD127–FoxP3+ cells within the CD4+ T cell population from allostimulated CD25–/dim cells. Interleukin (IL)‐2 receptor blocking prevented this induction. The ASC‐induced T cells (iTreg) inhibited effector cell proliferation as effectively as nTreg. The vast majority of cells within the iTreg fraction had a methylated FOXP3 gene Treg‐specific demethylated region (TSDR) indicating that they were not of nTreg origin. In conclusion, ASC induce Treg from effector T cells. These iTreg have immunosuppressive capacities comparable to those of nTreg. Their induction is IL‐2 pathway‐dependent. The dual effect of MSC of inhibiting immune cell proliferation while generating de‐novo immunosuppressive cells emphasizes their potential as cellular immunotherapeutic agent. 相似文献
6.
W. K. Yip M. A. Abdullah S. M. Yusoff H. F. Seow 《Clinical and experimental immunology》2009,155(3):412-422
The pathological significance of the mechanisms of tumour immune-evasion and/or immunosuppression, such as loss of T cell signalling and increase in regulatory T cells (Tregs), has not been well established in the nasopharyngeal carcinoma (NPC) microenvironment. To evaluate the Treg immunophenotypes in tumour-infiltrating lymphocytes (TILs), we performed a double-enzymatic immunostaining for detection of forkhead box P3 (FoxP3) and other markers including CD4, CD8, and CD25 on 64 NPC and 36 non-malignant nasopharyngeal (NP) paraffin-embedded tissues. Expression of CD3ζ and CD3ε was also determined. The prevalence of CD4+FoxP3+ cells in CD4+ T cells and the ratio of FoxP3+/CD8+ were increased significantly in NPC compared with those in NP tissues (P < 0·001 and P = 0·025 respectively). Moreover, the ratio of FoxP3+/CD25+FoxP3− in NPC was significantly lower than that in NP tissues (P = 0·005), suggesting an imbalance favouring activated phenotype of T cells in NPC. A significant negative correlation between the abundance of FoxP3+ and CD25+FoxP3− cells (P < 0·001) was also identified. When histological types of NPC were considered, a lower ratio of FoxP3+/CD25+FoxP3− was found in non-keratinizing and undifferentiated carcinomas. Increased CD4+FoxP3+/CD4+ proportion and FoxP3+/CD8+ ratio were associated with keratinizing squamous cell carcinoma. A reduced expression of CD3ζ in TILs was found in 20·6% of the NPC tissues but none of the NP tissues. These data provide evidence for the imbalances of Treg and effector T cell phenotypes and down-regulation of signal-transducing molecules in TILs, supporting their role in suppression of immune response and immune evasion of NPC. 相似文献
7.
8.
Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3+ regulatory T cells specific for the ubiquitous RNA‐binding nuclear antigen La/Sjögren's syndrome (SS)‐B
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Z.‐J. Pan C. G. Horton C. Lawrence A. D. Farris 《Clinical and experimental immunology》2016,186(1):18-29
RNA‐binding nuclear antigens are a major class of self‐antigen to which immune tolerance is lost in rheumatic diseases. Serological tolerance to one such antigen, La/Sjögren's syndrome (SS)‐B (La), is controlled by CD4+ T cells. This study investigated peripheral tolerance to human La (hLa) by tracking the fate of hLa‐specific CD4+ T cells expressing the transgenic (Tg) 3B5.8 T cell receptor (TCR) after adoptive transfer into lymphocyte‐replete recipient mice expressing hLa as a neo‐self‐antigen. After initial antigen‐specific cell division, hLa‐specific donor CD4+ T cells expressed forkhead box protein 3 (FoxP3). Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted interleukin (IL)?10 in vitro in response to antigenic stimulation. Transfer of highly purified FoxP3‐negative donor cells demonstrated that accumulation of hLa‐specific regulatory T cells (Treg) was due primarily to expansion of small numbers of donor Treg. Depletion of recipient plasmacytoid dendritic cells (pDC), but not B cells, severely hampered the accumulation of FoxP3+ donor Treg in hLa Tg recipients. Recipient pDC expressed tolerogenic markers and higher levels of co‐stimulatory and co‐inhibitory molecules than B cells. Adoptive transfer of hLa peptide‐loaded pDC into mice lacking expression of hLa recapitulated the accumulation of hLa‐specific Treg. Blockade of the type 1 interferon (IFN) receptor in hLa Tg recipients of hLa‐specific T cells impaired FoxP3+ donor T cell accumulation. Therefore, peripheral expansion of Treg specific for an RNA‐binding nuclear antigen is mediated by antigen‐presenting pDC in a type 1 IFN‐dependent manner. These results reveal a regulatory function of pDC in controlling autoreactivity to RNA‐binding nuclear antigens. 相似文献
9.
G. Fousteri T. Jofra I. Debernardis S. M. Stanford A. Laurenzi N. Bottini M. Battaglia 《Clinical and experimental immunology》2014,178(1):178-189
Protein tyrosine phosphatases (PTPs) regulate T cell receptor (TCR) signalling and thus have a role in T cell differentiation. Here we tested whether the autoimmune predisposing gene PTPN22 encoding for a PTP that inhibits TCR signalling affects the generation of forkhead box protein 3 (FoxP3)+ T regulatory (Treg) cells and T helper type 1 (Th1) cells. Murine CD4+ T cells isolated from Ptpn22 knock‐out (Ptpn22KO) mice cultured in Treg cell polarizing conditions showed increased sensitivity to TCR activation compared to wild‐type (WT) cells, and subsequently reduced FoxP3 expression at optimal‐to‐high levels of activation. However, at lower levels of TCR activation, Ptpn22KO CD4+ T cells showed enhanced expression of FoxP3. Similar experiments in humans revealed that at optimal levels of TCR activation PTPN22 knock‐down by specific oligonucleotides compromises the differentiation of naive CD4+ T cells into Treg cells. Notably, in vivo Treg cell conversion experiments in mice showed delayed kinetic but overall increased frequency and number of Treg cells in the absence of Ptpn22. In contrast, the in vitro and in vivo generation of Th1 cells was comparable between WT and Ptpn22KO mice, thus suggesting PTPN22 as a FoxP3‐specific regulating factor. Together, these results propose PTPN22 as a key factor in setting the proper threshold for FoxP3+ Treg cell differentiation. 相似文献
10.
11.
Decreased frequencies and impaired functions of the CD31+ subpopulation in Treg cells associated with decreased FoxP3 expression and enhanced Treg cell defects in patients with coronary heart disease
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
L. Huang Y. Zheng X. Yuan Y. Ma G. Xie W. Wang H. Chen L. Shen 《Clinical and experimental immunology》2017,187(3):441-454
12.
Th17, synchronically increased with Tregs and Bregs,promoted by tumour cells via cell‐contact in primary hepatic carcinoma
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
W. Wang Z. Wang Y. Qin G. Tang G. Cai Y. Liu J. Zhang P. Zhang Q. Shen L. Shen W. Yu 《Clinical and experimental immunology》2018,192(2):181-192
Documented reports about T helper type 17 (Th17) cells have revealed that Th17 plays a critical role in inflammation and autoimmunity diseases. However, the role of Th17 in cancer remains contradictory. The interplay between Th17 and tumour cells in the tumour microenvironment of primary hepatic carcinoma (PHC) needs to be explored further and the relationship between Th17, regulatory T cells (Tregs) and regulatory B cells (Bregs) has not been defined completely. In this study, numerous experiments were undertaken to elucidate the interaction of Th17 and Treg/Breg cells involved in PHC. Our work demonstrated that an increased Th17 was detected in the peripheral circulation and in tumour tissues in PHC patients. In addition, increases in peripheral blood Th17 corresponded with tumour–node–metastasis (TNM) stage progression. Also, further studies indicated that Th17 cells were promoted by tumour cells in the PHC tumour microenvironment through both contact‐dependent and ‐independent mechanisms, but cell‐contact played the major important role in promoting the production and proliferation of Th17. When isolated CD4+CD25+CD127low Tregs and CD4+CD25–CD127+ non‐Tregs were cultured with autologous tumour cells, it implied that the phenotype of Th17 and Tregs was modified by tumour cells in the tumour microenvironment. As well as this, Th17 cells were also found to correlate positively with CD4+forkhead box protein 3+ Tregs and CD19+CD5+CD1dhi Bregs in PHC. Notably, Th17 increased synchronically with Tregs and Bregs in PHC. These findings may provide new clues to reveal the mechanisms of immune escape in PHC. 相似文献
13.
N. Yokobori C. Sabio y García R. Musella J. Castagnino M. C. Sasiain S. de la Barrera 《Clinical and experimental immunology》2014,175(2):235-245
Tuberculous pleural effusion is characterized by a T helper type 1 (Th1) profile, but an excessive Th1 response may also cause tissue damage that might be controlled by regulatory mechanisms. In the current study we investigated the role of regulatory T cells (Treg) in the modulation of Th1 responses in patients with tuberculous (TB) pleurisy. Using flow cytometry we evaluated the proportion of Treg (CD4+CD25highforkhead box protein 3+), interferon (IFN)‐γ and interleukin (IL)‐10 expression and CD107 degranulation in peripheral blood (PB) and pleural fluid (PF) from patients with TB pleurisy. We demonstrated that the proportion of CD4+CD25+, CD4+CD25highFoxP3+ and CD8+CD25+ cells were increased in PF compared to PB samples. Mycobacterium tuberculosis stimulation increased the proportion of CD4+CD25low/negIL‐10+ in PB and CD4+CD25low/negIFN‐γ+ in PF; meanwhile, CD25high mainly expressed IL‐10 in both compartments. A high proportion of CD4+CD107+ and CD8+CD107+ cells was observed in PF. Treg depletion enhanced the in‐vitro M. tuberculosis‐induced IFN‐γ and CD4+ and CD8+ degranulation responses and decreased CD4+IL‐10+ cells in PF. Our results demonstrated that in TB pleurisy Treg cells effectively inhibit not only IFN‐γ expression but also the ability of CD4+ and CD8+ cells to degranulate in response to M. tuberculosis. 相似文献
14.
Z. Wang B.‐Y. Shi Y.‐Y. Qian M. Cai Q. Wang 《Clinical and experimental immunology》2009,155(3):496-503
CD4+CD25+ forkhead box P3 (FoxP3)+regulatory T (Treg) cells are generated and play a key role in the induction and maintenance of transplant tolerance in organ recipients. It has been proposed that interleukin (IL)-2/IL-2 receptor (IL-2R) signalling was essential for the development and proliferation of antigen-activated T cells that included both effector T cells and Treg cells. Basiliximab (Simulect™), a chimeric monoclonal antibody directed against the α-chain of the IL-2R (CD25), can be expected to not only affect alloreactive effector T cells, but also reduce the number and function of Treg cells. We therefore examined the effect of basiliximab induction therapy on the number and function of the Treg cells in renal recipients. Basiliximab decreased the percentage of CD4+CD25+T cells, but failed to influence the percentage of CD4+FoxP3+ Treg cells. The cellular CD25 expression was decreased significantly by basiliximab injection, but CD4+CD25+ T cells was not depleted from the circulating pool through monoclonal antibody activation-associated apoptosis. Functional analysis revealed that inhibitory function of Treg cells from recipients with basiliximab injection was not significantly different from recipients without injection. These data indicate that the functional Treg population may not be influenced by short-term basiliximab treatment. 相似文献
15.
Harnessing the power of regulatory T‐cells to control autoimmune diabetes: overview and perspective
下载免费PDF全文
![点击此处可从《Immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Type 1 diabetes (T1D) is a T‐cell‐mediated autoimmune disease resulting in islet β‐cell destruction, hypoinsulinaemia and severely altered glucose homeostasis. Although the mechanisms that initiate T1D still remain elusive, a breakdown of immune tolerance between effector T‐cells (Teff) and regulatory T‐cells (Treg) is considered to be the crucial component leading to autoimmunity. As such, strategies have been developed to boost the number and/or function of Treg in the hope of specifically hampering the pathogenic Teff activity. In this review, we will summarize the current understanding of biomarkers and functions of both forkhead box protein 3 (FoxP3)+ Treg and type 1 regulatory T (Tr1) cells in health and in T1D, examine the outcome of experimental therapies in both animal models and humans via manipulation of Treg responses and also provide an outlook on the potential of Treg‐based immunotherapies in the prevention and treatment of this disease. Discussed immunotherapies include adoptive transfer of ex‐vivo expanded FoxP3+ Treg, manipulation of Treg cells via the interleukin (IL)‐2/IL‐2R pathway and induction of Treg by tolerogenic peptides, tolerogenic dendritic cells or altered gut microbiota. 相似文献
16.
RORγt expression in Tregs promotes systemic lupus erythematosus via IL‐17 secretion,alteration of Treg phenotype and suppression of Th2 responses
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
T. Ramcke B. Goerke M. C. Meyer C. Wegscheid M. Luig G. Tiegs R. A. K. Stahl O. M. Steinmetz 《Clinical and experimental immunology》2017,188(1):63-78
17.
Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
N. Costa O. Marques S. I. Godinho C. Carvalho B. Leal A. M. Figueiredo C. Vasconcelos A. Marinho M. F. Moraes‐Fontes A. Gomes da Costa C. Ponte R. Campanilho‐Marques T. Cóias A. R. Martins J. F. Viana M. Lima B. Martins C. Fesel 《Clinical and experimental immunology》2017,189(3):318-330
Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)‐2 receptor alpha chain]. Low‐dose IL‐2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg) subsets in 45 SLE patients, 103 SLE‐unaffected first‐degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25‐encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+FoxP3+CD45RO–CD31+ recent thymic emigrant Tregs. This first component effect influenced the proportions of circulating CD4+FoxP3highCD45RO+ activated Tregs. (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up‐regulated CD25 strongly in these cells during differentiation from naive Tregs, SLE patients specifically failed to do so. This CD25 up‐regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs, but not to their circulating numbers. Both effects were found related to T cell IL‐2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up‐regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg‐directed therapies can be monitored more effectively when taking this distinction into account. 相似文献
18.
19.
Cell‐penetrable mouse forkhead box protein 3 alleviates experimental arthritis in mice by up‐regulating regulatory T cells
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Xia Liu Baoju Ji Mengyi Sun Weijiang Wu Lili Huang Aihua Sun Yangyong Zong Sheng Xia Liyun Shi Hui Qian Wenrong Xu Qixiang Shao 《Clinical and experimental immunology》2015,181(1):87-99
20.
Regulatory T cell frequencies are increased in preterm infants with clinical early‐onset sepsis
下载免费PDF全文
![点击此处可从《Clinical and experimental immunology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
J. Pagel A. Hartz J. Figge C. Gille S. Eschweiler K. Petersen L. Schreiter J. Hammer C. M. Karsten D. Friedrich E. Herting W. Göpel J. Rupp C. Härtel 《Clinical and experimental immunology》2016,185(2):219-227
The predisposition of preterm neonates to invasive infection is, as yet, incompletely understood. Regulatory T cells (Tregs) are potential candidates for the ontogenetic control of immune activation and tissue damage in preterm infants. It was the aim of our study to characterize lymphocyte subsets and in particular CD4+CD25+forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well‐phenotyped preterm infants (n = 117; 23 + 0 – 36 + 6 weeks of gestational age) in the first 3 days of life in comparison to term infants and adults. We demonstrated a negative correlation of Treg frequencies and gestational age. Tregs were increased in blood samples of preterm infants compared to term infants and adults. Notably, we found an increased Treg frequency in preterm infants with clinical early‐onset sepsis while cause of preterm delivery, e.g. chorioamnionitis, did not affect Treg frequencies. Our data suggest that Tregs apparently play an important role in maintaining maternal‐fetal tolerance, which turns into an increased sepsis risk after preterm delivery. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics. 相似文献