Regulatory CD4<sup>+</sup>CD25<sup>+</sup>T-cells are Controlled by Multiple Pathways at Multiple Levels

Qu, Yanyan; Zhao, Yong

doi:10.1080/08830180701365917

Cited by 16 publications

(8 citation statements)

References 82 publications

(100 reference statements)

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“…Recently, researchers have investigated whether depletion of a subset of T lymphocytes called regulatory T lymphocytes (Tregs) can potentiate immunotherapies against cancer. Tregs are a subpopulation of CD4 + T lymphocytes that constitutively express the transcription factor Foxp3, the high affinity IL2 receptor CD25 and the B7 ligand CTLA4 [20]. Tregs are required for the maintenance of tolerance throughout the lifetime of the organism [21] and mutations in Foxp3 are known to cause acute autoimmune disorders in humans [22].…”

Section: Introductionmentioning

confidence: 99%

Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

et al. 2008

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BackgroundRegulatory T lymphocytes (Treg) infiltrate human glioblastoma (GBM); are involved in tumor progression and correlate with tumor grade. Transient elimination of Tregs using CD25 depleting antibodies (PC61) has been found to mediate GBM regression in preclinical models of brain tumors. Clinical trials that combine Treg depletion with tumor vaccination are underway to determine whether transient Treg depletion can enhance anti-tumor immune responses and improve long term survival in cancer patients.FindingsUsing a syngeneic intracrabial glioblastoma (GBM) mouse model we show that systemic depletion of Tregs 15 days after tumor implantation using PC61 resulted in a decrease in Tregs present in tumors, draining lymph nodes and spleen and improved long-term survival (50% of mice survived >150 days). No improvement in survival was observed when Tregs were depleted 24 days after tumor implantation, suggesting that tumor burden is an important factor for determining efficacy of Treg depletion in clinical trials. In a T cell dependent model of brain tumor regression elicited by intratumoral delivery of adenoviral vectors (Ad) expressing Fms-like Tyrosine Kinase 3 ligand (Flt3L) and Herpes Simplex Type 1-Thymidine Kinase (TK) with ganciclovir (GCV), we demonstrate that administration of PC61 24 days after tumor implantation (7 days after treatment) inhibited T cell dependent tumor regression and long term survival. Further, depletion with PC61 completely inhibited clonal expansion of tumor antigen-specific T lymphocytes in response to the treatment.ConclusionsOur data demonstrate for the first time, that although Treg depletion inhibits the progression/eliminates GBM tumors, its efficacy is dependent on tumor burden. We conclude that this approach will be useful in a setting of minimal residual disease. Further, we also demonstrate that Treg depletion, using PC61 in combination with immunotherapy, inhibits clonal expansion of tumor antigen-specific T cells, suggesting that new, more specific targets to block Tregs will be necessary when used in combination with therapies that activate anti-tumor immunity.

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Section: Introductionmentioning

confidence: 99%

Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

et al. 2008

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“…Consistent with our findings, Miura reported that alloantigen stimulation significantly upregulated expression of CD134 and FoxP3 on CD4 lymphocytes [ 34 ]. CD134 was shown to regulate Treg function since administration of CD134 antibody abrogated suppression mediated by Tregs in a GvHD model, in addition to its participation in development and homeostasis of Tregs [ 35 ]. Expression of CD278 was shown to define subsets of Tregs with differences in cytokine production [ 36 ], as well as viability and suppressive capability [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

Bioimaging of alloantigen-stimulated regulatory T cells in rat vascularized composite allotransplantation

et al. 2018

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BackgroundTipping the balance toward regulatory T cells (Tregs) through adoptive cell therapy has shown promise to induce transplantation tolerance. Although such strategy has been explored in many mice organ transplantation studies, less knowledge was available in rat systems. Furthermore, the behaviors of the transferred cells have not been well studied in real-time fashion.MethodsTregs from naïve LEW rats were purified in two steps with the autoMACS system. Immunosuppression potential of these cells was examined with mixed lymphocyte reaction. Following stimulation by the alloantigen in vitro, the purified Tregs were infused into the recipients of vascularized composite allotransplantation (VCA). Secondary allogeneic skin grafting challenge was performed on the recipients with long-term survived VCA. Live optical imaging was performed to track luciferase-expressing Tregs following infusion to the VCA recipients. Expression of relevant molecules was studied by flow cytometry or quantitative RT-PCR.ResultsRat Tregs were enriched following two-step cell sorting and showed immunosuppressive capacity. Upon infusion into the VCA recipients that have been treated with antilymphocyte serum and short-term Cyclosporin A, the antigen-stimulated Tregs significantly prolonged VCA survival and induced donor-specific tolerance. Tracking of the infused bioluminescent Tregs showed their specific homing to lymph nodes, and then to the VCAs. Following secondary skin grafting, Tregs specifically gathered at the donor-derived skin that was not rejected by the recipient. The in vivo migratory pattern coincided with the altered expression of cell surface molecules of CD62L, CD103, CD134, and CD278, following donor-antigen stimulation. Elevated expression of CCR4 and CCL22 in allograft may also participate in recruiting Tregs for maintenance of VCA survival and promoting donor-specific tolerance.ConclusionSorted Tregs induced donor-specific tolerance to VCA in rats. Live cell tracking demonstrated that activated CD4+CD25+FoxP3+ Tregs targeted primarily to the lymph nodes and VCA. The Tregs migrated to the secondary grafted donor skin and contributed to the maintenance of donor-specific tolerance. These behaviors were associated with phenotypic changes induced by donor antigen stimulation. Increased expression of CCR4 and CCL22 in VCA skin may also be relevant.

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“…Immunosuppressive CD4 + CD25 + Foxp3 + Treg cells play crucial roles in the maintenance of self-immune tolerance and keep host proper intensity of immune response (Qu and Zhao 2007;. Decreased numbers and/or functional deficiency of CD4 + CD25 + Foxp3 + Treg cells result in development of a variety of autoimmune diseases like multiple sclerosis and type I diabetes (Wang et al 2006;Zeng et al 2012;Miyara et al 2014).…”

Section: Mmg Exposure On Cd4 + Cd25 + Treg Cellsmentioning

confidence: 99%

The Distinctive Sensitivity to Microgravity of Immune Cell Subpopulations

Chen

Luo

Liu

et al. 2015

Microgravity Sci. Technol.

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Immune dysfunction in astronauts is well documented after spaceflights. Microgravity is one of the key factors directly suppressing the function of immune system. However, it is unclear which subpopulations of immune cells including innate and adaptive immune cells are more sensitive to microgravity. We herein investigated the direct effects of modeled microgravity (MMg) on different immune cells in vitro. Mouse splenocytes, thymocytes and bone marrow cells were exposed to MMg for 16 hrs. The survival and the phenotypes of different subsets of immune cells including CD4 + T cells, CD8 + T cells, CD4 + Foxp3 + regulatory T cells (Treg), B cells, monocytes/macrophages, dendritic cells (DCs), natural killer cells (NK) were determined by flow cytometry. After splenocytes were cultured under MMg for 16h, the cell frequency and total numbers Electronic supplementary material The online version of this article (of monocytes, macrophages and CD4 + Foxp3 + T cells were significantly decreased more than 70 %. MMg significantly decreased the cell numbers of CD8 + T cells, B cells and neutrophils in splenocytes. The cell numbers of CD4 + T cells and NK cells were unchanged significantly when splenocytes were cultured under MMg compared with controls. However, MMg significantly increased the ratio of mature neutrophils to immature neutrophils in bone marrow and the cell number of DCs in splenocytes. Based on the cell survival ability, monocytes, macrophages and CD4 + Foxp3 + Treg cells are most sensitive to microgravity; CD4 + T cells and NK cells are resistant to microgravity; CD8 + T cells and neutrophils are impacted by short term microgravity exposure. Microgravity promoted the maturation of neutrophils and development of DCs in vitro. The present studies offered new insights on the direct effects of MMg on the survival and homeostasis of immune cell subsets.

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Regulatory CD4⁺CD25⁺T-cells are Controlled by Multiple Pathways at Multiple Levels

Cited by 16 publications

References 82 publications

Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Bioimaging of alloantigen-stimulated regulatory T cells in rat vascularized composite allotransplantation

The Distinctive Sensitivity to Microgravity of Immune Cell Subpopulations

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Regulatory CD4+CD25+T-cells are Controlled by Multiple Pathways at Multiple Levels

Cited by 16 publications

References 82 publications

Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Treg Depletion Inhibits Efficacy of Cancer Immunotherapy: Implications for Clinical Trials

Bioimaging of alloantigen-stimulated regulatory T cells in rat vascularized composite allotransplantation

The Distinctive Sensitivity to Microgravity of Immune Cell Subpopulations

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Regulatory CD4⁺CD25⁺T-cells are Controlled by Multiple Pathways at Multiple Levels