CD4+CD25+ T cells as immunoregulatory T cells in vitro

Chai, Jian-Guo; Tsang, Julia Yuen Shan; Lechler, Robert I.; Simpson, Elizabeth; Dyson, Julian; Scott, Diane

doi:10.1002/1521-4141(200208)32:8<2365::aid-immu2365>3.0.co;2-2

Cited by 48 publications

(29 citation statements)

References 21 publications

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“…In DO11.10 mice, 4 -6% of CD4 ϩ T cells constitutively express CD25, which was consistent with previous findings (25,34). Our analysis revealed that the majority of CD4 ϩ CD25 ϩ T cells in these animals express the transgenic TCR as defined by staining with the KJ1-26 Ab.…”

Section: Discussionsupporting

confidence: 92%

CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

Jaffar

Sivakuru

Roberts

2004

The Journal of Immunology

109

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We used a TCR-transgenic mouse to investigate whether Th2-mediated airway inflammation is influenced by Ag-specific CD4+CD25+ regulatory T cells. CD4+CD25+ T cells from DO11.10 mice expressed the transgenic TCR and mediated regulatory activity. Unexpectedly, depletion of CD4+CD25+ T cells before Th2 differentiation markedly reduced the expression of IL-4, IL-5, and IL-13 mRNA and protein when compared with unfractionated (total) CD4+ Th2 cells. The CD4+CD25−-derived Th2 cells also expressed decreased levels of IL-10 but were clearly Th2 polarized since they did not produce any IFN-γ. Paradoxically, adoptive transfer of CD4+CD25−-derived Th2 cells into BALB/c mice induced an elevated airway eosinophilic inflammation in response to OVA inhalation compared with recipients of total CD4+ Th2 cells. The pronounced eosinophilia was associated with reduced levels of IL-10 and increased amounts of eotaxin in the bronchoalveolar lavage fluid. This Th2 phenotype characterized by reduced Th2 cytokine expression appeared to remain stable in vivo, even after repeated exposure of the animals to OVA aerosols. Our results demonstrate that the immunoregulatory properties of CD4+CD25+ T cells do extend to Th2 responses. Specifically, CD4+CD25+ T cells play a key role in modulating Th2-mediated pulmonary inflammation by suppressing the development of a Th2 phenotype that is highly effective in vivo at promoting airway eosinophilia. Conceivably, this is partly a consequence of regulatory T cells facilitating the production of IL-10.

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Section: Discussionsupporting

confidence: 92%

CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

Jaffar

Sivakuru

Roberts

2004

The Journal of Immunology

109

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“…Thus, a plausible explanation for the lack of AICD in Tregs is diminished or absent CD95L expression. However, contradictory results regarding CD95L expression by Tregs have been obtained (16,(25)(26)(27)) that prompted us to investigate CD95L surface protein expression in Tregs compared with that in Tcons by a highly sensitive flow cytometry protocol. Tcons displayed high CD95L surface protein upon stimulation for 20 h with anti-CD3 Ab on day 6 of in vitro culture and upon P/I treatment on both day 0 (freshly isolated) and day 6 of culture ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

Weiß

Schmidt

Vobis

et al. 2011

The Journal of Immunology

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CD4+CD25++Foxp3+ regulatory T cells (Tregs) control self-reactive cells to maintain peripheral tolerance. Treg homeostasis has to be controlled tightly to ensure balanced Treg-mediated suppression. One mechanism that regulates the CD4+ T cell pool is activation-induced cell death (AICD). This is mimicked in vitro by TCR restimulation-induced expression of the death ligand CD95L (FasL/APO-1L/CD178) in expanded T cells. These cells express the death receptor CD95 (Fas/APO-1), and binding of CD95L to CD95 results in AICD. In contrast, Tregs do not undergo AICD upon TCR (re)stimulation in vitro despite a functional CD95 cell death pathway. In this study, we show that human and murine Tregs express low levels of CD95L upon stimulation. Knockdown of the transcriptional repressor Foxp3 partially rescues CD95L expression and AICD in human Tregs. Moreover, upon stimulation Foxp3-mutant Tregs from Scurfy mice express CD95L similar to conventional T cells. We further addressed whether exogenous CD95 stimulation provides a mechanism of Treg homeostatic control in vivo in mice. Triggering of CD95 reduced Treg numbers systemically as reflected by in vivo imaging and decreased GFP+ Treg numbers ex vivo. Our study reveals that Foxp3 negatively regulates CD95L expression in Tregs and demonstrates that Tregs are susceptible to homeostatic control by CD95 stimulation.

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“…Anti-CTLA-4 does not, however, successfully reverse in vitro suppression in all studies (Chai et al, 2002;Thornton and Shevach, 1998). Studies with human cultured cells have suggested that CTLA-4 blockade has only a moderate or no effect on the suppressive function of CD4 + CD25 + regulatory T cells (Annunziato et al, 2002;Levings et al, 2001b).…”

Section: Ctla-4 As a Non Cell-autonomous Regulator: Regulatory T Cellmentioning

confidence: 98%

Checkpoint Blockade in Cancer Immunotherapy

Korman¹,

Peggs

Allison

2006

Advances in Immunology

518

364

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The progression of a productive immune response requires that a number of immunological checkpoints be passed. Passage may require the presence of excitatory costimulatory signals or the avoidance of negative or coinhibitory signals, which act to dampen or terminate immune activity. The immunoglobulin superfamily occupies a central importance in this coordination of immune responses, and the CD28/cytotoxic T-lymphocyte antigen-4 (CTLA-4):B7.1/B7.2 receptor/ligand grouping represents the archetypal example of these immune regulators. In part the role of these checkpoints is to guard against the possibility of unwanted and harmful self-directed activities. While this is a necessary function, aiding in the prevention of autoimmunity, it may act as a barrier to successful immunotherapies aimed at targeting malignant self-cells that largely display the same array of surface molecules as the cells from which they derive. Therapies aimed at overcoming these mechanisms of peripheral tolerance, in particular by blocking the inhibitory checkpoints, offer the potential to generate antitumor activity, either as monotherapies or in synergism with other therapies that directly or indirectly enhance presentation of tumor epitopes to the immune system. Such immunological molecular adjuvants are showing promise in early clinical trials. This review focuses on the results of the archetypal example of checkpoint blockade, anti-CTLA-4, in preclinical tumor models and clinical trials, while also highlighting other possible targets for immunological checkpoint blockade.

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CD4+CD25+ T cells as immunoregulatory T cells in vitro

Cited by 48 publications

References 21 publications

CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

CD4+CD25+ T Cells Regulate Airway Eosinophilic Inflammation by Modulating the Th2 Cell Phenotype

Foxp3-Mediated Suppression of CD95L Expression Confers Resistance to Activation-Induced Cell Death in Regulatory T Cells

Checkpoint Blockade in Cancer Immunotherapy

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