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Cell surface levels of endothelial ICAM‐1 influence the transcellular or paracellular T‐cell diapedesis across the blood–brain barrier
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Michael Abadier Neda Haghayegh Jahromi Ludmila Cardoso Alves Rémy Boscacci Dietmar Vestweber Scott Barnum Urban Deutsch Britta Engelhardt Ruth Lyck 《European journal of immunology》2015,45(4):1043-1058
The extravasation of CD4+ effector/memory T cells (TEM cells) across the blood–brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM‐1 and ICAM‐2 are essential for CD4+ TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM‐1 in determining the cellular route of CD4+ TEM‐cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow. Inflammatory conditions, inducing high levels of endothelial ICAM‐1, promoted rapid initiation of transcellular diapedesis of CD4+ T cells across the BBB, while intermediate levels of endothelial ICAM‐1 favored paracellular CD4+ T‐cell diapedesis. Importantly, the route of T‐cell diapedesis across the BBB was independent of loss of BBB barrier properties. Unexpectedly, a low number of CD4+ TEM cells was found to cross the inflamed BBB in the absence of endothelial ICAM‐1 and ICAM‐2 via an obviously alternatively regulated transcellular pathway. In vivo, this translated to the development of ameliorated EAE in ICAM‐1null//ICAM‐2?/?C57BL/6J mice. Taken together, our study demonstrates that cell surface levels of endothelial ICAM‐1 rather than the inflammatory stimulus or BBB integrity influence the pathway of T‐cell diapedesis across the BBB. 相似文献
3.
Yufei Wang Thomas Seidl Trevor Whittall Kaboutar Babaahmady Thomas Lehner 《European journal of immunology》2010,40(6):1628-1638
Evidence is presented that thermal or oxidizing stress‐activated DC interact with CD4+ T cells to induce and maintain a TCR‐independent homeostatic memory circuit. Stress‐activated DC expressed endogenous intra‐cellular and cell surface HSP70. The NF‐κB signalling pathway was activated and led to the expression of membrane‐associated IL‐15 molecules. These interacted with the IL‐15 receptor complex on CD4+ T cells, thus activating the Jak3 and STAT5 phosphorylation signalling pathway to induce CD40 ligand expression, T‐cell proliferation and IFN‐γ production. CD40 ligand on CD4+ T cells in turn re‐activated CD40 molecules on DC, inducing DC maturation and IL‐15 expression thereby maintaining the feedback circuit. The proliferating CD4+ T cells were characterized as CD45RA? CD62L+ central memory cells, which underwent homeostatic proliferation. The circuit is independent of antigen and MHC‐class‐II‐TCR interaction as demonstrated by resistance to TCR inhibition by ZAP70 inhibitor or MHC‐class II antibodies. These findings suggest that stress can activate a DC‐CD4+ T‐cell interacting circuit, which may be responsible for maintaining a homeostatic antigen‐independent memory. 相似文献
4.
Hyo Jung Nam Mi‐Young Song Dong‐Hoon Choi Se‐Hwan Yang Hyun‐Tak Jin Young‐Chul Sung 《European journal of immunology》2010,40(2):351-358
IL‐7 plays a crucial role in the homeostatic proliferation, differentiation and survival of T cells, as well as in the survival and proliferation of precursor B cells. Here, we demonstrated that utilizing nonlytic Fc‐fused IL‐7 (IL‐7‐Fcm) as a genetic adjuvant significantly enhanced not only CD4+ but also CD8+ T‐cell responses by E7 DNA immunization, in addition to improving protection against TC‐1‐induced tumors in comparison to IL‐7 alone. Similar results were obtained in OT‐1 adoptive transfer experiments with OVA DNA injection, suggesting independence from antigenic nature and experimental conditions. In particular, the increased frequency of CD8+ T cells was mainly due to enhanced T‐cell proliferation in T‐cell priming, and not to decreased cellular apoptosis. Interestingly, the enhanced adjuvant effect was not seen in the co‐delivery of lytic Fc‐fused IL‐7 (IL‐7‐Fc) which increases T‐cell apoptosis as well as T‐cell proliferation, suggesting that the T‐cell proliferative effect may be neutralized by T‐cell apoptosis. Thus, our findings suggest that nonlytic Fc, in contrast to lytic Fc, fusion to cytokines may provide an insight in designing a potent genetic adjuvant for inducing CD4+ and CD8+ T‐cell responses. 相似文献
5.
Hossein Keshavarz Valian Mahmoud Nateghi Rostami Minoo Tasbihi Akram Miramin Mohammadi Seyed Ebrahim Eskandari Abdolfattah Sarrafnejad Ali Khamesipour 《Journal of clinical immunology》2013,33(1):220-234
Purpose
The profile of central (=TCM) and effector (=TEM) memory CD4+ T cell subsets and the possible role as surrogate markers of protection is studied in the volunteers with history of cutaneous leishmaniasis (HCL).Methods
Profile of T cell subsets based on CCR7/CD45RA expressions and phenotypic changes after soluble Leishmania antigen (SLA) stimulation were analyzed. Then, sorted CD4+CD45RO?CD45RA+ naïve T, CD4+CD45RO+CD45RA?CCR7? TEM, CD4+CD45RO+CD45RA?CCR7+ TCM subsets were cultured with SLA for proliferation, cytokine production and intracellular cytokine assays.Results
In the HCL and control volunteers, the mean frequencies of CD4+CD45RA+CCR7+ naïve T cells and CD4+CD45RA?CCR7? TEM cells were higher than the other subsets before culture. Frequency of naïve T cells and CD4+CD45RA?CCR7+ TCM cells was significantly decreased (P?=?0.01 for naïve T and P?<?0.05 for TCM cells) and frequency of TEM cells was significantly increased after SLA stimulation compared to before culture (P?<?0.001). By CFSE labeling, CD4+CD45RO+CD45RA?CCR7+ TCM cells showed more proliferation potential than CD4+CD45RO+CD45RA?CCR7? TEM cells. Stimulation of the TEM cells in HCL volunteers induced a significantly higher IFN-γ production (P?=?0.04) with higher number of intracellular IFN-γ positive cells (P?=?0.032) than the same cells from controls. A significantly higher number of TCM cells produced IL-2 in HCL volunteers compared with controls (P?<?0.05). Most of the intracellular IFN-γ positive TEM cells were proliferating CFSE-dim populations (P?<?0.05).Conclusions
A combination of Leishmania-reactive IFN-γ producing CD4+CD45RO+CD45RA?CCR7? TEM and Leishmania-reactive IL-2 producing CD4+CD45RO+CD45RA?CCR7+ TCM are identified in individuals with history of CL which might play a role in protective recall immune response against Leishmania infection. 相似文献6.
S Lee T Hammond M W Watson J P Flexman W Cheng S Fernandez P Price 《Clinical and experimental immunology》2010,161(1):118-126
The proportions and activation status of T cells may influence responses to hepatitis C virus (HCV) and treatment outcome in patients receiving pegylated interferon (IFN)‐α/ribavirin therapy. We confirmed that IFN‐γ enzyme‐linked immunospot (ELISPOT) responses to HCV are poor in HCV patients and showed that responses to HCV and cytomegalovirus (CMV) antigens decrease during therapy. This was most apparent in patients with sustained virological response (SVR). Baseline frequencies of CD4+ effector memory (TEM) T cells were lower in SVR than non‐SVR. Proportions of CD4+ and CD8+ TEM and terminally differentiated effector memory (TEMRA) T cells declined on therapy in SVR, as did proportions of Fas+ CD8+ TEMRA T cells. Baseline frequencies of programmed death (PD)‐1‐expressing CD4+ TEM and TEMRA T‐cells were higher in SVR. Therapy increased percentages of PD‐1+ CD4+ central memory (TCM) T cells and PD‐1+ CD8+ TEM and TEMRA T cells in SVR. We conclude that successful therapy depletes circulating antigen‐specific CD4+ T cell responses. This paralleled decreases in proportions of effector memory T cells and higher percentages of CD4+ TCM T cells expressing PD‐1. 相似文献
7.
Almeida AR Ciernik IF Sallusto F Lanzavecchia A 《European journal of immunology》2010,40(12):3478-3488
Peripheral T‐cell expansion is of major relevance for immune function after lymphopenia. In order to promote regeneration, the process should result in a peripheral T‐cell pool with a similar subpopulation structure as before lymphopenia. We investigated the repopulation of the CD8+ central‐memory T cells (TCM) and effector‐memory T cells (TEM) pools after adoptive transfer of sorted CD8+ T cells from naïve, TCM and TEM subsets into T‐cell‐deficient hosts. We show that the initial kinetics of expansion are distinct for each subset and that the contribution to the repopulation of the CD8+ T‐cell pool by the progeny of each subset is not a mere function of its initial expansion. We demonstrate that CD4+CD25+ Treg play a major role in the repopulation of the CD8+ T‐cell pool and that CD8+ T‐cell subsets impact on each other. In the absence of CD4+CD25+ Treg, a small fraction of naïve CD8+ T cells strongly proliferates, correlating with further expansion and differentiation of co‐expanding CD8+ T cells. CD4+CD25+ Treg suppress these responses and lead to controlled repopulation, contributing decisively to the maintenance of recovered TCM and TEM fractions, and leading to repopulation of each pool with progeny of its own kind. 相似文献
8.
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
9.
G. Rosignoli C. H. Lim M. Bower F. Gotch N. Imami 《Clinical and experimental immunology》2009,157(1):90-97
Human immunodeficiency virus (HIV)‐1 causes T cell anergy and affects T cell maturation. Various mechanisms are responsible for impaired anti‐HIV‐1‐specific responses: programmed death (PD)‐1 molecule and its ligand PD‐L1 are negative regulators of T cell activity and their expression is increased during HIV‐1 infection. This study examines correlations between T cell maturation, expression of PD‐1 and PD‐L1, and the effects of their blockade. Peripheral blood mononuclear cells (PBMC) from 24 HIV‐1+ and 17 uninfected individuals were phenotyped for PD‐1 and PD‐L1 expression on CD4+ and CD8+ T cell subsets. The effect of PD‐1 and PD‐L1 blockade on proliferation and interferon (IFN)‐γ production was tested on eight HIV‐1+ patients. Naive (CCR7+CD45RA+) CD8+ T cells were reduced in HIV‐1 aviraemic (P = 0·0065) and viraemic patients (P = 0·0130); CD8 T effector memory subsets [CCR7‐CD45RA–(TEM)] were increased in HIV‐1+ aviraemic (P = 0·0122) and viraemic (P = 0·0023) individuals versus controls. PD‐1 expression was increased in CD4 naive (P = 0·0496), central memory [CCR7+CD45RA– (TCM); P = 0·0116], TEM (P = 0·0037) and CD8 naive T cells (P = 0·0133) of aviraemic HIV‐1+versus controls. PD‐L1 was increased in CD4 TEMRA (CCR7‐CD45RA+, P = 0·0119), CD8 TEM (P = 0·0494) and CD8 TEMRA (P = 0·0282) of aviraemic HIV‐1+versus controls. PD‐1 blockade increased HIV‐1‐specific proliferative responses in one of eight patients, whereas PD‐L1 blockade restored responses in four of eight patients, but did not increase IFN‐γ‐production. Alteration of T cell subsets, accompanied by increased PD‐1 and PD‐L1 expression in HIV‐1 infection contributes to anergy and impaired anti‐HIV‐1‐specific responses which are not rescued when PD‐1 is blocked, in contrast to when PD‐L1 is blocked, due possibly to an ability to bind to receptors other than PD‐1. 相似文献
10.
Wallace DL Bérard M Soares MV Oldham J Cook JE Akbar AN Tough DF Beverley PC 《Immunology》2006,119(2):243-253
Interleukin (IL)‐7 and IL‐15 are cytokines implicated in homeostatic control of the peripheral CD8 T‐cell pool. We compared the effects of IL‐7 and IL‐15 on survival and proliferation of purified human CD8+ T‐cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl‐2 up‐regulation. Surprisingly, although minimal proliferation of naïve CD8+ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL‐15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8+ T cells through several cell divisions resulted in up‐regulation of telomerase and the maintenance of telomere length. These data show that IL‐7 and IL‐15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset‐dependent manner, and have implications for the homeostatic expansion of the naïve CD8+ T‐cell pool. 相似文献
11.
CMV drives the expansion of highly functional memory T cells expressing NK‐cell receptors in renal transplant recipients
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Nandini Makwana Bree Foley Sonia Fernandez Silvia Lee Ashley Irish Hanspeter Pircher Patricia Price 《European journal of immunology》2017,47(8):1324-1334
Cytomegalovirus (CMV) is a common opportunistic infection encountered in renal transplant recipients (RTRs) and may be reactivated without symptoms at any time post‐transplant. We describe how active and latent CMV affect T‐cell subsets in RTRs who are stable on maintenance therapy. T‐cell responses to CMV were assessed in RTRs (n = 54) >2 years post‐transplant, and healthy controls (n = 38). Seven RTRs had CMV DNA detectable in plasma. CMV antibody and DNA aligned with increased proportions of CD8+ T cells and reduced CD4/CD8 ratios. This paralleled an expansion of effector memory T‐cell (TEM), terminally differentiated T‐cell (TEMRA) and CD57+ TEMRA cell populations. Expression of NK‐cell receptors, LIR‐1 and KLRG1 on CD4+ and CD8+ CD57+ TEM and TEMRA cells correlated with elevated interferon‐γ and cytotoxic responses to anti‐CD3 and increased cytotoxic responses to CMV phosphoprotein (pp) 65 in RTRs who carried CMV DNA. CD8+ T cells from all CMV seropositive RTRs responded efficiently to CMV immediate early (IE) ‐1 peptides. The data show that latent and active CMV infection can alter T‐cell subsets in RTRs many years after transplantation, and up‐regulate T‐cell expression of NK‐cell receptors. This may enhance effector responses of CD4+ and CD8+ T cells against CMV. 相似文献
12.
The transduction pattern of IL‐12‐encoding lentiviral vectors shapes the immunological outcome
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Cleo Goyvaerts Katrijn Broos David Escors Carlo Heirman Geert Raes Patrick De Baetselier Kris Thielemans Karine Breckpot 《European journal of immunology》2015,45(12):3351-3361
In situ modification of antigen‐presenting cells garnered interest in cancer immunotherapy. Therefore, we developed APC‐targeted lentiviral vectors (LVs). Unexpectedly, these LVs were inferior vaccines to broad tropism LVs. Since IL‐12 is a potent mediator of antitumor immunity, we evaluated whether this proinflammatory cytokine could enhance antitumor immunity of an APC‐targeted LV‐based vaccine. Therefore, we compared subcutaneous administration of broad tropism LVs (VSV‐G‐LV) with APC‐targeted LVs (DC2.1‐LV)‐encoding enhanced GFP and ovalbumin, or IL‐12 and ovalbumin in mice. We show that codelivery of IL‐12 by VSV‐G‐LVs or DC2.1‐LVs augments CD4+ or CD8+ T‐cell proliferation, respectively. Furthermore, we demonstrate that codelivery of IL‐12 enhances the CD4+ TH1 profile irrespective of its delivery mode, while an increase in cytotoxic and therapeutic CD8+ T cells was only induced upon VSV‐G‐LV injection. While codelivery of IL‐12 by DC2.1‐LVs did not enhance CD8+ T‐cell performance, it increased expression of inhibitory checkpoint markers Lag3, Tim3, and PD‐1. Finally, the discrepancy between CD4+ T‐cell stimulation with and without functional CD8+ T‐cell stimulation by VSV‐G‐ and DC2.1‐LVs is partly explained by the observation that IL‐12 relieves CD8+ T cells from CD4+ T‐cell help, implying that a TH1 profile is of minor importance for antitumor immunotherapy if IL‐12 is exogenously delivered. 相似文献
13.
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
14.
Memory CD8+ T cells colocalize with IL‐7+ stromal cells in bone marrow and rest in terms of proliferation and transcription
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Özen Sercan Alp Sibel Durlanik Daniel Schulz Mairi McGrath Joachim R. Grün Marcus Bardua Koichi Ikuta Evridiki Sgouroudis René Riedel Sandra Zehentmeier Anja E. Hauser Motokazu Tsuneto Fritz Melchers Koji Tokoyoda Hyun‐Dong Chang Andreas Thiel Andreas Radbruch 《European journal of immunology》2015,45(4):975-987
15.
《Mucosal immunology》2008,1(5):389-398
Induction of effective memory T cells is likely to be critical to the level and duration of protection elicited by novel live oral typhoid vaccines. Using cells from volunteers who ingested Salmonella Typhi vaccine strain CVD 909, we characterized the induction of interferon (IFN)-γ-secreting central (TCM, CD45RO+CD62L+) and effector (TEM, CD45RO+CD62L−) memory T populations, and their gut-homing potential based on integrin α4/β7 expression. Both CD4+ TEM and TCM populations secreted IFN-γ. However, although CD4+ TEM expressed, or not, integrin α4/β7, CD4+ TCM cells were predominantly integrin α4/β7+. In contrast, IFN-γ-secreting CD8+ cells were predominantly classical TEM and CD45RA+ TEM (TEMRA, CD45RO−CD62L−) subsets. However, although CD8+ TEM expressed, or not, integrin α4/β7, CD8+ TEMRA were predominantly integrin α4/β7+. This is the first demonstration that oral immunization of humans with S. Typhi elicits diverse IFN-γ-secreting CD4+ and CD8+ TCM and TEM subsets able to migrate to the gut and other lymphoid tissues. 相似文献
16.
Homeostasis of memory T cells 总被引:13,自引:0,他引:13
Charles D. Surh Onur Boyman Jared F. Purton Jonathan Sprent 《Immunological reviews》2006,211(1):154-163
Summary: The pool of memory T cells is regulated by homeostatic mechanisms to persist for prolonged periods at a relatively steady overall size. Recent work has shown that two members of the common γ chain (γc) family of cytokines, interleukin‐7 (IL‐7) and IL‐15, govern homeostasis of memory T cells. These two cytokines work in conjunction to support memory T‐cell survival and intermittent background proliferation. Normal animals contain significant numbers of spontaneously arising memory‐phenotype (MP) cells, though whether these cells are representative of true antigen‐specific memory T cells is unclear. Nevertheless, it appears that the two types of memory cells do not display identical homeostatic requirements. For antigen‐specific memory CD8+ T cells, IL‐7 is primarily important for survival while IL‐15 is crucial for their background proliferation. For memory CD4+ T cells, IL‐7 has an important role, whereas the influence of IL‐15 is still unclear. 相似文献
17.
P. Szodoray G. Papp I. F. Horvath S. Barath S. Sipka B. Nakken M. Zeher 《Clinical and experimental immunology》2009,157(3):343-349
The aim of the present study was to describe subsets of cells with regulatory properties in primary Sjögren's syndrome (pSS), and to correlate these cell populations with clinical symptoms. Among the 32 investigated patients, 23 had extraglandular manifestations (EGMs), while nine had only glandular symptoms. Twenty healthy individuals served as controls. The percentages of natural killer (NK), natural killer T cells (NK T), interleukin (IL)‐10 producing T regulatory type 1 (Tr1) cells and CD4+CD25+ regulatory T cells (Treg) cells were determined by flow cytometry and serum cytokine levels of IL‐4, IL‐6, IL‐10, tumour necrosis factor (TNF)‐α and interferon (IFN)‐γ were evaluated by enzyme‐linked immunosorbent assay (ELISA). Functional tests were carried out to assess the suppressor properties of Treg cells in patients and controls. Peripheral NK, NK T and Tr1 cell percentages were elevated in pSS, while CD4+CD25+ Treg cells showed reduced frequencies in patients compared to controls. In pSS, elevated percentages of NK T, Tr1 and CD4+CD25+ Treg cells were observed in patients with EGMs, when compared to patients with sicca symptoms only. CD4+CD25+ Treg cell percentages showed a negative correlation with sialometry values. The in vitro functional assay demonstrated lower suppression activity of CD4+CD25+ Treg cells in patients compared to controls. Serum IL‐6 and TNF‐α levels were elevated, while IL‐10 was decreased in patients compared to controls. Negative correlation was found between IL‐10 levels and the percentages of Tr1 cells. Changes in the investigated subsets of regulatory cells in pSS may contribute to the development and progression of the disease. 相似文献
18.
Immunosuppressive evidence of Tityus serrulatus toxins Ts6 and Ts15: insights of a novel K+ channel pattern in T cells
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Manuela B. Pucca Thaís B. Bertolini Felipe A. Cerni Karla C. F. Bordon Steve Peigneur Jan Tytgat Vânia L. Bonato Eliane C. Arantes 《Immunology》2016,147(2):240-250
The voltage‐gated potassium channel Kv1.3 is a novel target for immunomodulation of autoreactive effector memory T cells, which play a major role in the pathogenesis of autoimmune diseases. In this study, the Ts6 and Ts15 toxins isolated from Tityus serrulatus (Ts) were investigated for their immunosuppressant roles on CD4+ cell subsets: naive, effector (TEF), central memory (TCM) and effector memory (TEM). The electrophysiological assays confirmed that both toxins were able to block Kv1.3 channels. Interestingly, an extended Kv channel screening shows that Ts15 blocks Kv2.1 channels. Ts6 and Ts15 significantly inhibit the proliferation of TEM cells and interferon‐γ production; however, Ts15 also inhibits other CD4+ cell subsets (naive, TEF and TCM). Based on the Ts15 inhibitory effect of proliferation of all CD4+ cell subsets, and based on its blocking effect on Kv2.1, we investigated the Kv2.1 expression in T cells. The assays showed that CD4+ and CD8+ cells express the Kv2.1 channels mainly extracellularly with TCM cells expressing the highest number of Kv2.1 channels. We also provide in vivo experimental evidence to the protective effect of Ts6 and Ts15 on delayed‐type hypersensitivity reaction. Altogether, this study presents the immunosuppressive behaviour of Ts6 and Ts15 toxins, indicating that these toxins could be promising candidates for autoimmune disease therapy. Moreover, this is the first report illustrating the involvement of a novel K+ channel subtype, Kv2.1, and its distribution in T‐cell subsets. 相似文献
19.
Angela M. Crawley Agatha Vranjkovic Charlene Young Jonathan B. Angel 《European journal of immunology》2010,40(5):1396-1407
Signaling via the IL‐7 receptor complex (IL‐7Rα/CD127 and IL‐2Rγ/CD132) is required for T‐cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL‐2Rγ‐sharing (γC) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL‐2, IL‐4, IL‐7, IL‐15) and in humans (IL‐2, IL‐7), suggesting a common function. IL‐4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL‐4 in regulating CD127 expression and IL‐7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL‐4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane‐bound CD127 mRNA expression. Pre‐treatment of thymocytes or CD8+ T cells with IL‐4 inhibited IL‐7‐mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL‐4 is a potential contributor to impaired CD8+ T‐cell function in some anti‐viral and anti‐tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL‐7 activity is impaired and IL‐4 concentrations are elevated. 相似文献
20.
M. F. Macedo G. Porto M. Costa C. P. Vieira B. Rocha E. Cruz 《Clinical and experimental immunology》2010,159(3):363-371
Low CD8+ T lymphocyte numbers have long been described in hereditary haemochromatosis (HH). Recently, two conserved haplotypes localized near the microsatellite D6S105 at the major histocompatibility complex (MHC) class I region were described predicting the clinical expression of HH and the CD8+ T lymphocyte numbers. The A‐A‐T haplotype was associated with a severe clinical expression of HH and low CD8+ T lymphocyte numbers, while the G‐G‐G haplotype was associated with a milder clinical expression of HH and high CD8+ T lymphocyte numbers. As CD8+ T lymphocytes are a very heterogeneous population, in this study we analysed the CD8+ subpopulations of naive, central memory (TCM) and effector memory (TEM), and further subsets of CD8+ TEM cells in 47 HH patients and 68 controls. In addition, association studies were conducted between the conserved haplotypes and the CD8+ T cell subpopulations in HH. Variations of the numbers of naive and central memory cells with age were similar between HH patients and controls. For TEM cells and the TEM CD27‐CD28‐ subset no effect of age was observed in HH [R2 = 0·001, not significant (n.s.) and R2 = 0·01, n.s., respectively] contrasting with the increasing of these subpopulations with age in controls (R2 = 0·09, P = 0·017 and R2 = 0·22, P = 0·0005, respectively). Interestingly, patients homozygous for the A‐A‐T haplotype have lower numbers of CD8+ TEM cells due especially to lower numbers of TEM CD27‐CD28‐ (0·206 ± 0·119 and 0·066 ± 0·067 × 106 cells/ml, respectively) than patients carrying the G‐G‐G haplotype (0·358 ± 0·195 and 0·246 ± 0·202 × 106 cells/ml, respectively). This may suggest an inability of HH patients to differentiate the CD8+ T cells into the most mature phenotype. 相似文献