Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Yang, Xiaofeng

doi:10.2741/2775

Cited by 51 publications

(77 citation statements)

References 251 publications

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“…Preliminary data suggesting that dietary modification may reduce the levels of oxLDL and increase the levels of IgM PC antibodies [93] certainly increases the interest in determining whether high levels of IgM mLDL antibodies may have a beneficial effect on the evolution of atherosclerosis. Alternative interventions could involve controlled upregulation of T regulatory cells (Tregs), which has a strong theoretical appeal [94,95], and has been reported as an effective form of manipulation of transplant rejections responses [96], but is a rather distant target at this time. The only practical approach at this time is to reduce the antigenic load, either by dietary modification, or by pharmacological means.…”

Section: Discussionmentioning

confidence: 99%

Atherogenesis and the humoral immune response to modified lipoproteins

Virella¹,

Lopes‐Virella²

2008

Atherosclerosis

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Modified forms of LDL are immunogenic and activate both cell-mediated and humoral immune responses. Both types of responses are pro-inflammatory and are probably primary players in the perpetuation of the chronic inflammatory reaction characteristic of atherosclerosis. The immunologic response to modified LDL can be directed to MHC-II-associated peptides in the case of T helper cells, and to a variety of epitopes -modified lysine groups, modified phospholipids, proteins that become associated with oxidized LDL (such as β2GP1) -in the case of B cell responses. T cell activation is likely to play a major role through cross-activation of macrophages. Humoral responses to modified LDL are pathogenic as a consequence of the formation of antigen-antibody complexes containing modified LDL and IgG antibodies. Those immune complexes induce cholesterol ester accumulation in macrophages and macrophage-like cells, and induce the release of proinflammatory cytokines, chemokines, oxygen active radicals, and matrix metalloproteinases from those cells. There is no conclusive evidence supporting a protective role for IgM antibodies in humans, possibly because autoantibodies to modified lipoproteins are predominantly of the IgG isotype.

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Section: Discussionmentioning

confidence: 99%

Atherogenesis and the humoral immune response to modified lipoproteins

Virella¹,

Lopes‐Virella²

2008

Atherosclerosis

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“…However, IL-2-regulated Treg apoptotic pathways that underlie homeostatic mechanisms of Tregs remain poorly defined. Since homeostasis of Tregs is critical in maintaining immune tolerance and regulation of immune responses, elucidation of Treg-specific apoptotic pathways is significant (15). Our recent report showed that expression of pro-apoptotic protein Bax in Tregs is higher than that in CD4+CD25− T cells in the absence of any stimuli, which may be responsible for higher apoptosis rates of Tregs (10).…”

Section: Discussionmentioning

confidence: 99%

“…Previous reports have shown that Tregs are highly susceptible to apoptosis (15,34). Since Tregs generate poorly endogenous IL-2(7), Tregs require exogenous IL-2 for survival by expressing high levels of IL-2 receptor.…”

Section: Discussionmentioning

confidence: 99%

Higher expression of Bax in regulatory T cells increases vascular inflammation

Xiong

Song²,

Yan³

et al. 2008

Front Biosci

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This study is to examine our hypothesis that CD4+CD25 high Foxp3+ regulatory T cells (Tregs) have an interleukin-2 (IL-2) withdrawal-triggered apoptosis pathway, and modulation of Treg apoptosis pathway affects development of vascular inflammation. We found that pro-apoptotic protein Bax upregulation in Tregs is induced by IL-2 withdrawal. Treg apoptosis induced by IL-2 withdrawal is inhibited by a Bax inhibitor, suggesting that highly expressed Bax is functional. To define the role of upregulated Bax in Treg apoptosis, we established a Tregs-specific Bax transgenic mouse model. Enforced expression of Bax in Tregs promotes Treg apoptosis triggered by IL-2 withdrawal and other apoptosis stimuli, suggesting pro-apoptotic role of highly expressed Bax in wild-type Tregs. Finally, higher expression of Bax in Tregs decreases the striking threshold of vascular inflammation due to the failure of suppression of inflammatory cells resulting from Treg apoptosis. These results have demonstrated the proof of principle that the modulation of Tregs apoptosis/survival could be used as a new therapeutic approach for inflammatory cardiovascular diseases. KeywordsRegulatory T Cells; Apoptosis; Bax; Inflammation; Vasculitis INTRODUCTIONCD4+CD25 high Foxp3+ regulatory T cells (Tregs), comprising 5-10% of CD4+ T cells(1), exhibit potent immunosuppressive functions(2) in the regulation of autoimmunity and inflammatory atherosclerosis (3,4). Naturally occurring Treg cells (thymus-generated, nTreg cells), as an independent subset, are engaged in the maintenance of immunological selftolerance and inhibition of various immune responses (5) and inflammatory atherogenesis. nTregs (Tregs in the rest of paper) appear to have specific apoptosis pathways since Treg cells have higher susceptibility to apoptosis (6), especially to IL-2 withdrawal-induced apoptosis. Tregs are poor IL-2 producers(7), implying that insufficient paracrine IL-2 supply to Tregs in pathological conditions could be responsible for higher susceptibility of Tregs to apoptosis. However, intracellular regulation of IL-2 insufficiency-triggered Treg apoptosis remains poorly defined. The Bcl-2/Bcl-xL protein family members play a central role in the Send correspondence to: Xiao-Feng Yang, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, MRB, Rm. 325, Philadelphia, PA 19140, Tel: 215-707-5985, Fax: 215-707-7068 MATERIALS AND METHODS Construction of CD25+ T cell-targeting mouse IL-2Rα promoter-Bax transgenic miceMouse IL-2 receptor α chain (CD25) promoter −2539 to +93 (GenBank Accession Number: M16398) vector pmIL2Rα-CAT1 (6.9 kb) was generously provided by P. Reichenbach and M. Nabholz(14). The construction of the CD25+ T cell targeting vector pCD25-Tg was described previously (10). The transgenic vector pCD25-Bax-Tg was verified by DNA sequencing by SeqWright Company (Houston, TX). The 3.818 kb transgenic DNA fragment "Nru I-CD25 promoter-C-Myc-Bax-Sex AI" was prepared by digesting the pCD25-Bax-Tg vector with three restrict...

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“…37 Therefore, enhanced recruitment of antitumor effector T lymphocytes to tumor tissue, in addition to inhibition of local regulatory T cells, may be an ideal target for improving cancer immunotherapy. [30][31][32][33][34][38][39][40] Strategies aimed at depletion/functional inhibition of these cells by molecular targeting must maintain a critical balance between tumor immunity and self-tolerance. 34,[41][42][43][44] These immunomodulation pathways may therefore have potential applications in forthcoming treatments of cancer.…”

Section: Regulatory T Cells In Endometrial Cancer/chang Et Almentioning

confidence: 99%

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

Chang

Huang

et al. 2010

Cancer

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BACKGROUND: A study was carried out to determine the functional attributes of CD4 þ CD25 þ regulatory T cells in cancer progression by suppressing antitumor immunity. METHODS: Triple-color flow cytometry was used to study the phenotype expression of CD4 þ CD25 þ regulatory T cells and CD8 þ T cells in the peripheral blood lymphocytes (PBLs) and tumor-infiltrating lymphocytes (TILs) of 57 cases of stage I to IV endometrial carcinoma. The expression of T cell subsets was correlated with clinical prognostic parameters. RESULTS: The prevalence of CD4 þ CD25 þ T cells was significantly higher in the TILs than PBLs. The expression of CD4 þ CD25 þ regulatory T cells in cancer milieu correlated with the tumor grade, stage, and myometrium invasion. The expression of FOXP3 and GITR in CD4 þ CD25 þ regulatory T cells was lower in PBLs than TILs. Most tumor-infiltrating CD8 þ T cells were CD28 À CD45RA À CD45RO þ CCR7 À , suggesting good terminal differentiation. Most of them had an activated role with CD69 þ CD103 þ CD152 þ . Functionally, both granzyme B and perforin were scarcely expressed in peripheral regulatory T cells but were highly expressed in peripheral regulatory T cells in the tumor microenvironment. In contrast, CD8 þ cytotoxic T cells derived from PBLs expressed both granzyme B and perforin, and at significantly higher levels than in TILs. Further functional assays demonstrated that Th1 cytokines and cytotoxic molecules can be synchronously up-regulated in CD8 þ cytotoxic T cells. CONCLUSIONS: Regulatory T cells in the tumor microenvironment may abrogate CD8 þ T cell cytotoxicity in a granzyme B-and perforin-dependent conduit. Decreases in both Th1 cytokines and cytotoxic enzymes are relevant for regulatory T cell-mediated restraint of tumor clearance in vivo. Of clinical significance, the expression of regulatory T cells in TILs may mediate T cell immune repression within cancer milieu and thus greatly correlate with cancer progression. Cancer 2010;116:5777-88.

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Factors regulating apoptosis and homeostasis of CD4+CD25highFOXP3+ regulatory T cells are new therapeutic targets

Cited by 51 publications

References 251 publications

Atherogenesis and the humoral immune response to modified lipoproteins

Atherogenesis and the humoral immune response to modified lipoproteins

Higher expression of Bax in regulatory T cells increases vascular inflammation

Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma

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