Inhibition of Notch1 induces population and suppressive activity of regulatory T cell in inflammatory arthritis
Bo Youn ChoiYuri ChoiJong Sung ParkLi‐Jung KangSeung Hyun BaekJin Su ParkGahee BahnYoonsuk ChoHark Kyun KimJihoon HanJae Hoon SulSang-Ha BaikDong Hoon HyunThiruma V. ArumugamSiyoung YangJeung-Whan HanYoung Mo KangYong-Woo ChoJae Hyung ParkDong‐Gyu Jo
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Abstract:
Inhibition of Notch signalling has shown anti-inflammatory properties in vivo and in vitro models of rheumatoid arthritis (RA). The objective of this study was to determine whether Notch1 might play a role in regulating T-regulatory cells (Tregs) in animal models of RA. Methods: Collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) were induced in C57BL/6, Notch1 antisense transgenic (NAS) or DBA1/J mice. We examined whether pharmacological inhibitors of γ-secretase (an enzyme required for Notch1 activation) and antisense-mediated knockdown of Notch1 could attenuate the severity of inflammatory arthritis in CIA and CAIA mice. Proportions of CD4+CD25+Foxp3+ Treg cells were measured by flow cytometry. To assess the suppressive capacity of Treg toward responder cells, CFSE-based suppression assay of Treg was performed. Results: γ-secretase inhibitors and antisense-mediated knockdown of Notch1 reduced the severity of inflammatory arthritis in both CIA and CAIA mice. Pharmacological and genetic inhibition of Notch1 signalling induced significant elevation of Treg cell population in CIA and CAIA mice. We also demonstrated that inhibition of Notch signalling suppressed the progression of inflammatory arthritis through modulating the expansion and suppressive function of regulatory T (Treg) cells. Conclusion: Pharmacological and genetic inhibition of Notch1 signalling suppresses the progression of inflammatory arthritis through modulating the population and suppressive function of Treg cells in animal models of RA.Keywords:
Regulatory T cell
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CD4+CD25high regulatory T (Treg) cells are crucial for immune homeostasis and peripheral tolerance, but their relevance to allergic asthma has not been fully elucidated.To assess peripheral blood CD4+ T cells, and CD4+CD25highCD127low Treg cells expressing phenotypic markers (FoxP3, GITR, CTLA-4, and FAS) in allergic asthma subjects.Peripheral blood mononuclear cells were isolated from 60 allergic asthma (AA) subjects and 30 healthy controls (HC). We examined by flow cytometry, the proportion of CD4+ T cells and CD4+CD25highCD127low Treg cells as well as the expression of FoxP3, GITR, CTLA-4, and FAS by CD4+CD25highCD127low Treg cells. Moreover, FOXP3 mRNA expression was measured by quantitative real time polymerase chain reaction (real-time RT-PCR).The absolute number of CD4+CD25highCD127low Treg cells and the percentages of CD4+CD25highCD127low Treg cells expressing one of the four selected markers were significantly lower in allergic asthma subjects compared with controls. We observed no significant decreased absolute CD4+ T cell count in the examined groups compared to the control group. Except for GITR, circulatory CD4+CD25highCD127low Treg cells of severe allergic asthma (SA) subjects showed significantly lower expressions of FoxP3, CTLA-4, and CD95 than did those isolated from mild to moderate asthma (MA) patients. There was no statistically significant difference in the level of mRNA FoxP3 expression in CD4+CD25+ Treg cells between allergic asthma subjects and healthy controls groups, and within the examined groups (p>0.05).These findings suggest that allergic asthma and the use of glucocorticosteroids are associated with decreased absolute number of circulatory CD4+CD25highCD127low Treg cells and the decreased frequencies of CD4+CD25highCD127low Treg cells expressing one of the four selected markers.
Regulatory T cell
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Peripheral tolerance
Allergic Inflammation
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Objective:To analyse the expression level of peripheral blood regulatory T cell and helper T cell in pregnant women with intrahepatic cholestasis of pregnancy(ICP).Methods: A total of 23 ICP puerperas who had delivery in the hopsital recently were continuously selected,peripheral blood regulatory T cell(CD4+ CD25+ Treg and CD4+ CD25+ Foxp3+Treg) and helper T cell(CD+3,CD+4,CD+8,CD+4/ CD+8) were detected in all selected objects and compared with those of the normal pregnant women(control group,20 women).Results:For the regulatory T cell data,serum CD4+ CD25+ Treg and CD4+ CD25+ Foxp3+Treg level in ICP group were obviously lower than those of the control group(P0.05 to 0.01).For the helper T cell data,serum CD+4/ CD+8 expression level in ICP group was significantly higher than that of the control group,however,the expression level of CD+8 was obviously lower(P0.05 to 0.01).Conclusion:ICP puerperas have abnormal expression in both peripheral blood regulatory T cell and helper T cell.
Cholestasis of pregnancy
Regulatory T cell
Treg cell
T helper cell
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Abstract Declines in immune function are well described in the elderly and are considered to contribute significantly to the disease burden in this population. Regulatory T cells (Tregs), a CD4+ T cell subset usually characterized by high CD25 expression, control the intensity of immune responses both in rodents and humans. However, because CD25 expression does not define all Tregs, especially in aged hosts, we characterized Tregs by the expression of FOXP3, a transcription factor crucial for Treg differentiation and function. The proportion of FOXP3+CD4+ Tregs increased in the blood of the elderly and the lymphoid tissues of aged mice. The expression of functional markers, such as CTLA-4 and GITR, was either preserved or increased on FOXP3+ Tregs from aged hosts, depending on the tissue analyzed. In vitro depletion of peripheral Tregs from elderly humans improves effector T cell responses in most subjects. Importantly, Tregs from old FoxP3-GFP knock-in mice were suppressive, exhibiting a higher level of suppression per cell than young Tregs. The increased proportion of Tregs in aged mice was associated with the spontaneous reactivation of chronic Leishmania major infection in old mice, likely because old Tregs efficiently suppressed the production of IFN-γ by effector T cells. Finally, in vivo depletion of Tregs in old mice attenuated disease severity. Accumulation of functional Tregs in aged hosts could therefore play an important role in the frequent reactivation of chronic infections that occurs in aging. Manipulation of Treg numbers and/or activity may be envisioned to enhance the control of infectious diseases in this fragile population.
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Background A subset of T cells with immunosuppressive properties is the CD4+CD25+FOXP3+ regulatory T cells (Treg). Two main hypotheses explain Tregs in HIV-1 infection: one stating that Tregs prevent chronic immune activation, and hence are beneficial, and another regarding Tregs as harmful because they suppress anti-HIV immune responses. To gain more information on the role of Tregs in chronic HIV-1 infection, we are evaluating the Treg population in chronic HIV-1 infected patients on HAART, treatment naive viremic patients, and HIV-1 infected Elite Controllers (EC). Additionally, as Tregs are known to inhibit T cell activation, the T cell activation profile is also being tested.
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