共查询到20条相似文献,搜索用时 109 毫秒
1.
Semiletova NV Shen XD Feldman DM Gao F Mhoyan A Liu D Busuttil RW Kupiec-Weglinski JW Ghobrial RM 《Cellular immunology》2007,248(1):48-58
Functional topography of rat class I major histocompatibility complex (MHC) molecule was studied. The α1-helical sequences that are shared by class I RT1.Al and RT1.Au were substituted in the RT1.Aa molecule to produce the composite -RT1.Aa MHC class I allochimeric molecule. Dominant immunogenic epitopes that induce accelerated rejection were identified within the hypervariable regions of the α1 domain of RT1.Aa, RT1.Al, and RT1.Au. Peri-transplant portal venous delivery of MHC class I allochimeric proteins, that included composite α1 helical immunodominant epitopes of RT1.Au and RT1.Al, induced donor-specific tolerance to RT1u (Wistar Furth, WF) and RT1l Lewis, LEW) disparate cardiac allografts in ACI (RT1a) hosts. Allochimeric generated tolerance was characterized by absence of T cell deletion or anergy. Donor specific IgM allo-Abs was not detected, while IgG alloresponse was markedly attenuated in sera of tolerant hosts. Further, long-term allografts in allochimeric-conditioned hosts exhibited moderate B cell infiltration when compared to rejecting controls. Analysis of intragraft cytokines revealed selective upregulation of IL-10 and marked inhibition of IL-2, IFN-γ, and IL-4. Our findings indicate the emergence of a peripherally induced tolerant state, afforded by the novel approach of soluble class I allochimeric conditioning that presents donor immunogenic epitopes in the context of recipient class I determinants. 相似文献
2.
Wei Luo Jin Su Xiao-Bing Zhang Zhi Yang Ming-Qian Zhou Zhen-Min Jiang Pei-Pei Hao Su-Dong Liu Qian Wen Qi Jin Li Ma 《PloS one》2012,7(10)
Background
The importance of CD4+ and CD8+ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR β chain and omitted analysis of the Vα family even though α chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients.Methodology/Principal Findings
CDR3 spectratypes of CD4+ and CD8+ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions.Conclusions/Significance
Results from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients. 相似文献3.
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Wojciech Lisik Neelam Tejpal Yongquan Gong T. Spencer Skelton Malathesh Ganachari Eric G. Bremer Malgorzata Kloc Rafik M. Ghobrial 《PloS one》2009,4(12)
Background
The allochimeric MHC class I molecule [α1h1/u]-RT1.Aa that contains donor-type (Wistar Furth, WF; RT1u) epitopes displayed on recipient-type (ACI, RT1a) administered in conjunction with sub-therapeutic dose of cyclosporine (CsA) induces indefinite survival of heterotopic cardiac allografts in rat model. In vascularized transplantation models, the spleen contributes to graft rejection by generating alloantigen reactive T cells. The immune response in allograft rejection involves a cascade of molecular events leading to the formation of immunological synapses between T cells and the antigen-presenting cells.Methodology/Principal Findings
To elucidate the molecular pathways involved in the immunosuppressive function of allochimeric molecule we performed microarray and quantitative RTPCR analyses of gene expression profile of splenic T cells from untreated, CsA treated, and allochimeric molecule + subtherapeutic dose of CsA treated animals at day 1, 3 and 7 of post transplantation. Allochimeric molecule treatment caused down regulation of genes involved in actin filament polymerization (RhoA and Rac1), cell adhesion (Catna1, Vcam and CD9), vacuolar transport (RhoB, Cln8 and ATP6v1b2), and MAPK pathway (Spred1 and Dusp6) involved in tubulin cytoskeleton reorganization and interaction between actin and microtubule cytoskeleton. All these genes are involved in T cell polarity and motility, i.e., their ability to move, scan and to form functional immunological synapse with antigen presenting cells (APCs).Conclusions
These results indicate that the immunosuppressive function of allochimeric molecule may depend on the impairment of T cells'' movement and scanning ability, and possibly also the formation of immunological synapse. We believe that these novel findings may have important clinical implications for organ transplantation. 相似文献6.
Fabio Morandi Elisa Ferretti Paola Bocca Ignazia Prigione Lizzia Raffaghello Vito Pistoia 《PloS one》2010,5(7)
Background
In recent years, many immunoregulatory functions have been ascribed to soluble HLA-G (sHLA-G). Since chemotaxis is crucial for an efficient immune response, we have investigated for the first time the effects of sHLA-G on chemokine receptor expression and function in different human T cell populations.Methodology/Principal Findings
T cell populations isolated from peripheral blood were stimulated in the presence or absence of sHLA-G. Chemokine receptors expression was evaluated by flow cytometry. sHLA-G downregulated expression of i) CCR2, CXCR3 and CXCR5 in CD4+ T cells, ii) CXCR3 in CD8+ T cells, iii) CXCR3 in Th1 clones iv) CXCR3 in TCR Vδ2γ9 T cells, and upregulated CXCR4 expression in TCR Vδ2γ9 T cells. sHLA-G inhibited in vitro chemotaxis of i) CD4+ T cells towards CCL2, CCL8, CXCL10 and CXCL11, ii) CD8+ T cells towards CXCL10 and CXCL11, iii) Th1 clones towards CXCL10, and iv) TCR Vδ2γ9 T cells towards CXCL10 and CXCL11. Downregulation of CXCR3 expression on CD4+ T cells by sHLA-G was partially reverted by adding a blocking antibody against ILT2/CD85j, a receptor for sHLA-G, suggesting that sHLA-G downregulated chemokine receptor expression mainly through the interaction with ILT2/CD85j. Follicular helper T cells (TFH) were isolated from human tonsils and stimulated as described above. sHLA-G impaired CXCR5 expression in TFH and chemotaxis of the latter cells towards CXCL13. Moreover, sHLA-G expression was detected in tonsils by immunohistochemistry, suggesting a role of sHLA-G in local control of TFH cell chemotaxis. Intracellular pathways were investigated by Western Blot analysis on total extracts from CD4+ T cells. Phosphorylation of Stat5, p70 s6k, β-arrestin and SHP2 was modulated by sHLA-G treatment.Conclusions/Significance
Our data demonstrated that sHLA-G impairs expression and functionality of different chemokine receptors in T cells. These findings delineate a novel mechanism whereby sHLA-G modulates T cell recruitment in physiological and pathological conditions. 相似文献7.
Modeling the Ternary Complex TCR-Vβ/CollagenII(261–273)/HLA-DR4 Associated with Rheumatoid Arthritis
Maria Cristina De Rosa Bruno Giardina Caterina Bianchi Cristiana Carelli Alinovi Davide Pirolli Gianfranco Ferraccioli Maria De Santis Gabriele Di Sante Francesco Ria 《PloS one》2010,5(7)
Background
It is known that genetic predisposition to rheumatoid arthritis (RA) is associated with the MHC class II allele HLA-DR4 and that residues 261–273 of type II collagen (huCollp261) represent an immunodominant T cell epitope restricted by the DR4 molecule. Despite recent advances in characterization of MHC and T cell receptor (TCR) contacts to this epitope, the atomic details of TCR/huCollp261/HLA-DR4 ternary complex are not known.Methodology/Principal Findings
Here we have used computational modeling to get insight into this interaction. A three-dimensional model of the TCR Vβ domain from a DR4+ patient affected by RA has been derived by homology modeling techniques. Subsequently, the structure of the TCR Vβ domain in complex with huCollp261/HLA-DR4 was obtained from a docking approach in conjunction with a filtering procedure based on biochemical information. The best complex from the docking experiments was then refined by 20 ns of molecular dynamics simulation in explicit water. The predicted model is consistent with available experimental data. Our results indicate that residues 97–101 of CDR3β are critical for recognition of huCollp261/HLA-DR4 by TCR. We also show that TCR contacts on p/MHC surface affect the conformation of the shared epitope expressed by DR alleles associated with RA susceptibility.Conclusions/Significance
This work presents a three-dimensional model for the ternary complex TCR-Vβ/collagenII(261–273)/HLA-DR4 associated with rheumatoid arthritis that can provide insights into the molecular mechanisms of self reactivity. 相似文献8.
Objective
To study the association of anergic pulmonary tuberculosis with Vδ2+ T cells and related cytokine levels.Methods
82 pulmonary tuberculosis patients were divided into two groups according to their purified protein derivative tuberculin skin test (TST) results: 39 with TST-negative anergic pulmonary tuberculosis and 43 with TST-positive pulmonary tuberculosis, while 40 healthy volunteers were used as control. Based on chest X-ray results, the tuberculosis lesions were scored according to their severity, with a score of ≤ 2.5 ranking as mild, 2.5-6 as moderate and ≥ 6 as severe. The Vδ2+ T cell percentage and their expression levels of the apoptosis-related membrane surface molecule FasL in peripheral blood and bronchoalveolar lavage fluids (BALF) were analyzed by flow cytometry, while IL-2, IL-4, IL-6 and IL-10 cytokine and γ-interferon (γ-IFN) concentrations in peripheral blood were determined by ELISA.Results
Most of the patients with chest X-ray lesion scores higher than 6 belonged to the anergic tuberculosis group (P<0.05). Anergic pulmonary tuberculosis patients displayed reduced peripheral blood Vδ2+ T cell counts (P<0.05) and higher FasL expression in peripheral blood Vδ2 + T cells (P <0.05). The Vδ2+ T cell percentages in the BALF of all tuberculosis patients were lower than in their peripheral blood (P <0.05), and IL-4 and IL-10 concentrations in peripheral blood of anergic tuberculosis patients were higher than in TST-positive tuberculosis patients and healthy controls (P <0.05).Conclusion
Anergic pulmonary tuberculosis is accompanied by reduced Vδ2+ T cell percentage, and elevated Vδ2+ T cell FasL expression as well as enhanced IL-4 and IL-10 levels in peripheral blood. 相似文献9.
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Background
Thiazolidinediones (TZD) class of drugs, and 15-deoxy-D12,14-prostaglandin J2 (15d-PGJ2) are immune regulators predicted to modulate human autoimmune disease. Their effects on γδ T cells, which are involved in animal model and human and animal autoimmune diseases, are unknown.Methodology/Principal Findings
We characterized the activity of rosiglitazone (from the TZD class of drugs) and 15d-PGJ2 in human Vδ2 T cells. We found that 15d-PGJ2 and rosiglitazone had different effects on Vδ2 T cell functions. Both 15d-PGJ2 and rosiglitazone suppressed Vδ2 T cell proliferation in response to IPP and IL2. However, only 15d-PGJ2 suppressed functional responses including cytokine production, degranulation and cytotoxicity against tumor cells. The mechanism for 15d-PGJ2 effects on Vδ2 T cells acts through inhibiting Erk activation. In contrast, rosiglitazone did not affect Erk activation but the IL2 signaling pathway, which accounts for rosiglitazone suppression of IL2-dependent, Vδ2 T cell proliferation without affecting TCR-dependent functions. Rosiglitazone and 15d-PGJ2 are designed to be peroxisome proliferator-activated receptor gamma (PPARγ) ligands and PPARγ was expressed in Vδ2 T cell. Surprisingly, when PPARγ levels were lowered by specific siRNA, 15d-PGJ2 and rosiglitazone were still active, suggesting their target of action induces cellular proteins other than PPARγ.Conclusions/Significance
The current findings expand our understanding of how the immune system is regulated by rosiglitazone and 15d-PGJ2 and will be important to evaluate these compounds as therapeutic agents in human autoimmune disease. 相似文献11.
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Dual TCRα-expressing T cells outnumber dual TCRβ-expressing cells by ~10:1. As a result, efforts to understand how dual TCR T cells impact immunity have focused on dual TCRα expression; dual TCRβ expression remains understudied. We recently demonstrated, however, that dual TCRβ expression accelerated disease in a TCR transgenic model of autoimmune arthritis through enhanced positive selection efficiency, indicating that dual TCRβ expression, though rare, can impact thymic selection. Here we generated mice hemizygous for TCRα, TCRβ, or both on the C57BL/6 background to investigate the impact bi-allelic TCR chain recombination has on T cell development, repertoire diversity, and autoimmunity. Lack of bi-allelic TCRα or TCRβ recombination reduced αβ thymocyte development efficiency, and the absence of bi-allelic TCRβ recombination promoted γδ T cell development. However, we observed no differences in the numbers of naïve and expanded antigen-specific T cells between TCRα+/-β+/- and wildtype mice, and TCR repertoire analysis revealed only subtle differences in Vβ gene usage. Finally, the absence of dual TCR T cells did not impact induced experimental autoimmune encephalomyelitis pathogenesis. Thus, despite more stringent allelic exclusion of TCRβ relative to TCRα, bi-allelic TCRβ expression can measurably impact thymocyte development and is necessary for maintaining normal αβ/γδ T cell proportions. 相似文献
14.
Background
GABAA receptors (GABAAR) are composed of several subunits that determine sensitivity to drugs, synaptic localisation and function. Recent studies suggest that agonists targeting selective GABAAR subunits may have therapeutic value against the cognitive impairments observed in schizophrenia. In this study, we determined whether GABAAR binding deficits exist in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia and tested if changes in GABAAR binding are related to the changes in subunit mRNAs. The GABA orthosteric and the benzodiazepine allosteric binding sites were assessed autoradiographically using [3H]Muscimol and [3H]Flumazenil, respectively, in a large cohort of individuals with schizophrenia (n = 37) and their matched controls (n = 37). We measured, using qPCR, mRNA of β (β1, β2, β3), γ (γ1, γ2, γ2S for short and γ2L for long isoform, γ3) and δ subunits and used our previous measurements of GABAAR α subunit mRNAs in order to relate mRNAs and binding through correlation and regression analysis.Results
Significant increases in both [3H]Muscimol (p = 0.016) and [3H]Flumazenil (p = 0.012) binding were found in the DLPFC of schizophrenia patients. Expression levels of mRNA subunits measured did not show any significant difference in schizophrenia compared to controls. Regression analysis revealed that in schizophrenia, the [3H]Muscimol binding variance was most related to α4 mRNA levels and the [3H]Flumazenil binding variance was most related to γ2S subunit mRNA levels. [3H]Muscimol and [3H]Flumazenil binding were not affected by the lifetime anti-psychotics dose (chlorpromazine equivalent).Conclusions
We report parallel increases in orthosteric and allosteric GABAAR binding sites in the DLPFC in schizophrenia that may be related to a “shift” in subunit composition towards α4 and γ2S respectively, which may compromise normal GABAergic modulation and function. Our results may have implications for the development of treatment strategies that target specific GABAAR receptor subunits. 相似文献15.
Background
Toxic Shock Syndrome (TSS) is characterized by fever, rash, hypotension, constitutional symptoms, and multi-organ involvement and is caused by Staphylococcus aureus enterotoxins such as Staphylococcal Enterotoxin B (SEB). SEB binds to the MHC-IIα chain and is recognized by the TCRβ chain of the Vβ8 TCR+ T cells. The binding of SEB to Vβ chain results in rapid activation of T cells and production of inflammatory cytokines, such as Interleukin-2 (IL-2), Interferon-γ and Tumor Necrosis Factor-α which mediate TSS. Although IL2 was originally identified as the T cell growth factor and was proposed to contribute to T cell differentiation, its role in TSS remains unexplored.Methodology/Principal Findings
Mice were injected with D-Gal (25 mg/mouse). One hour after D-Galactosamine (D-Gal) injection each mouse was injected with SEB (20 µg/mouse. Mice were then observed for 72 hrs and death was recorded at different times. We tested Interleukin-12, IFNγ, and IL-2 deficient mice (IL-2−/−), but only the IL-2 deficient mice were resistant to SEB induced toxic shock syndrome. More importantly reconstitution of IL-2 in IL-2 deficient mice restored the shock. Interestingly, SEB induced IL-2 production from T cells was dependent on p38MAPK activation in macrophages as inhibition of it in macrophages significantly inhibited IL-2 production from T cells.Conclusion
This study shows the importance of IL -2 in TSS which has not been previously explored and it also shows that regulating macrophages function can regulate T cells and TSS. 相似文献16.
Background
The binding of the T cell receptor (TCR) to major histocompatibility complex (MHC) molecules in the thymus determines fates of TCRαβ lymphocytes that subsequently home to secondary lymphoid tissue. TCR transgenic models have been used to study thymic selection and lineage commitment. Most TCR transgenic mice express the rearranged TCRαβ prematurely at the double negative stage and abnormal TCRαβ populations of T cells that are not easily detected in non-transgenic mice have been found in secondary lymphoid tissue of TCR transgenic mice.Methodology and Principal Findings
To determine developmental pathways of TCR-transgenic thymocytes, we used Cre-LoxP-mediated fate mapping and show here that premature expression of a transgenic TCRαβ diverts some developing thymocytes to a developmental pathway which resembles that of gamma delta cells. We found that most peripheral T cells with the HY-TCR in male mice have bypassed the RORγt-positive CD4+8+ (double positive, DP) stage to accumulate either as CD4−8− (double negative, DN) or as CD8α+ T cells in lymph nodes or gut epithelium. Likewise, DN TCRαβ cells in lymphoid tissue of female mice were not derived from DP thymocytes.Conclusion
The results further support the hypothesis that the premature expression of the TCRαβ can divert DN thymocytes into gamma delta lineage cells. 相似文献17.
18.
Beverly Duncan Cristina Nazarov–Stoica Jacqueline Surls Margaret Kehl Constantin Bona Sofia Casares Teodor-D. Brumeanu 《PloS one》2010,5(7)
Background
Double negative CD3+4−8− TCRαβ splenic cells (DNCD3) can suppress the immune responses to allo and xenografts, infectious agents, tumors, and some autoimmune disorders. However, little is known about their role in autoimmune diabetes, a disease characterized by the reduction of insulin production subsequent to destruction of pancreatic β-cells by a polyclonal population of self-reactive T-cells. Herein, we analyzed the function and phenotype of DNCD3 splenic cells in young NOD mice predisposed to several autoimmune disorders among which, the human-like autoimmune diabetes.Methodology/Principal Findings
DNCD3 splenic cells from young NOD mice (1) provided long-lasting protection against diabetes transfer in NOD/Scid immunodeficient mice, (2) proliferated and differentiated in the spleen and pancreas of NOD/Scid mice and pre-diabetic NOD mice into IL-10-secreting TR-1 like cells in a Th2-like environment, and (3) their anti-diabetogenic phenotype is CD3+(CD4−CD8−)CD28+CD69+CD25low Foxp3− iCTLA-4−TCRαβ+ with a predominant Vβ13 gene usage.Conclusions/Significance
These findings delineate a new T regulatory component in autoimmune diabetes apart from that of NKT and CD4+CD25high Foxp3+T-regulatory cells. DNCD3 splenic cells could be potentially manipulated towards the development of autologous cell therapies in autoimmune diabetes. 相似文献19.
Cecilia Engdahl Anna E B?rjesson Huamei F Forsman Annica Andersson Alexandra Stubelius Andree Krust Pierre Chambon Ulrika Islander Claes Ohlsson Hans Carlsten Marie K Lagerquist 《Arthritis research & therapy》2014,16(4):R150
Introduction
Estrogen (E2) delays onset and decreases severity of experimental arthritis. The aim of this study was to investigate the importance of total estrogen receptor alpha (ERα) expression and cartilage-specific ERα expression in genetically modified mice for the ameliorating effect of estrogen treatment in experimental arthritis.Methods
Mice with total (total ERα-/-) or cartilage-specific (Col2α1-ERα-/-) inactivation of ERα and wild-type (WT) littermates were ovariectomized, treated with E2 or placebo, and induced with antigen-induced arthritis (AIA). At termination, knees were collected for histology, synovial and splenic cells were investigated by using flow cytometry, and splenic cells were subjected to a T-cell proliferation assay.Results
E2 decreased synovitis and joint destruction in WT mice. Amelioration of arthritis was associated with decreased frequencies of inflammatory cells in synovial tissue and decreased splenic T-cell proliferation. E2 did not affect synovitis or joint destruction in total ERα-/- mice. In Col2α1-ERα-/- mice, E2 protected against joint destruction to a similar extent as in WT mice. In contrast, E2 did not significantly ameliorate synovitis in Col2α1-ERα-/- mice.Conclusions
Treatment with E2 ameliorates both synovitis and joint destruction in ovariectomized mice with AIA via ERα. This decreased severity in arthritis is associated with decreased synovial inflammatory cell frequencies and reduced splenic T-cell proliferation. ERα expression in cartilage is not required for estrogenic amelioration of joint destruction. However, our data indicate that ERα expression in cartilage is involved in estrogenic effects on synovitis, suggesting different mechanisms for the amelioration of joint destruction and synovitis by E2. 相似文献20.
Yunda Huang Ann Duerr Nicole Frahm Lily Zhang Zoe Moodie Steve De Rosa M. Juliana McElrath Peter B. Gilbert 《PloS one》2014,9(11)