CTLA‐4 is required by CD4+CD25+ Treg to control CD4+ T‐cell lymphopenia‐induced proliferation

Sojka, Dorothy K.; Hughson, Angela; Fowell, Deborah J.

doi:10.1002/eji.200838603

Cited by 88 publications

(62 citation statements)

References 39 publications

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“…The Journal of Immunology 5891 decrease in IL-2 production by 5-d cultures with MSCs is consistent with other studies that reported on the inhibitory effects of MSCs on T cell proliferation (36,41,42). The mechanisms of suppression, especially cytokine involvement, are critical to further understand the findings in our study.…”

Section: Discussionsupporting

confidence: 90%

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Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Patel

Meyer

Greco

et al. 2010

The Journal of Immunology

358

291

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Mesenchymal stem cells (MSCs) have been shown to support breast cancer growth. Because MSCs also increase the frequency of regulatory T cells (Tregs), this study tested the hypothesis that human MSCs, via Tregs, protect breast cancer cells (BCCs) from immune clearance MSCs suppressed the proliferation of PBMCs when the latter were exposed to gamma-irradiated BCCs. Similarly, MSCs showed significant inhibition of PBMC migration toward BCCs and a corresponding decrease in CXCL12. MSCs also inhibited NK cell and CTL functions, which correlated with reduced numbers of CD8+ and CD56+ cells compared with parallel cultures without MSCs. The reduced NK and CTL activities correlated with a decrease in intracellular and secreted granzyme B. To explain these immunosuppressive findings, we compared Treg levels after coculture with MSCs and found an ∼2-fold increase in Tregs, with associated decreases in antitumor Th1 cytokines and increases in Th2 cytokines. MSC-derived TGF-β1 was largely responsible for the increase in Tregs based on knockdown studies. In the presence of Treg depletion, PBMC proliferation and effector functions were partially restored. Together, these studies show an MSC-mediated increase in Tregs in cocultures of PBMCs and BCCs. The results could be explained, in part, by the increase in Th2-type cytokines and MSC-generated TGF-β1. These findings demonstrate immune protection by MSCs to BCCs. The reduction in immune cell proliferation and recruitment mediated by MSCs has implications for treatment of breast cancer with chemotherapy.

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Section: Discussionsupporting

confidence: 90%

“…We next focused on IL-10 and TGF-b1 because they are both linked to T reg expansion and/or functions (35,36). The increase in IL-10 levels recorded by the arrays (Table I) was confirmed quantitatively by ELISA, and the results showed a significant increase in 5-d cultures (Fig.…”

Section: Cytokines In Mscs-mediated Effectsmentioning

confidence: 86%

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Patel

Meyer

Greco

et al. 2010

The Journal of Immunology

358

291

View full text Add to dashboard Cite

show abstract

“…Treg consumption of cytokines did not play a role; neither did the suppressive cytokines IL-10, TGF-β, or IL-35 ( Fig. S2) nor negative regulation via CTLA-4 (31). Tregs led to a selective defect in IFN-γ but not other Th1 cytokines such as TNF-α and lymphotoxin.…”

Section: Control Of Effector Function Independent Of Differentiation mentioning

confidence: 92%

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

Sojka

Fowell

2011

Proc. Natl. Acad. Sci. U.S.A.

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CD4 + CD25 + Forkhead box P3 (Foxp3) + regulatory T cells (Tregs) control immune responses to self and foreign antigens in secondary lymphoid organs and at tissue sites of inflammation. Tregs can modify the function of many immune cells and have been proposed to block early proliferation, differentiation, and effector function. Acute ablation of Tregs has revealed rapid cytokine production immediately after Treg removal, suggesting that Tregs may regulate effector function acutely rather than regulating the programming for immune function. We developed in vitro and in vivo models that enabled the direct test of Treg regulation of T-helper cell type 1 (Th1) differentiation. CD28 signaling is known to abrogate Treg suppression of IL-2 secretion and proliferation, but our studies show that Treg suppression of IFN-γ during Th1 priming proceeds despite enhanced CD28 signaling. Importantly, during Th1 differentiation, Tregs inhibited early IFN-γ transcription without disrupting expression of Th1-specific T-box transcription factor (Tbet) and Th1 programming. Acute shutoff of effector cytokine production by Tregs was selective for IFN-γ but not TNF-α and was independent of TGF-β and Epstein-Barr virus-induced gene 3. In vivo, Tregs potently controlled CD4 IFN-γ and CD4 effector cell expansion in the lymph node (four-to fivefold reduction) but not Th1 programming, independent of IL-10. Tregs additionally reduced CD4 IFN-γ in the inflamed dermis (twofold reduction) dependent on their production of IL-10. We propose a model for Treg inhibition of effector function based on acute cytokine regulation. Interestingly, Tregs used different regulatory mechanisms to regulate IFN-γ (IL-10-dependent or -independent) subject to the target T-cell stage of activation and its tissue location.

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“…Contact-dependent mechanisms are critical in vitro, since physical separation between Tregs and conventional T cells abrogates Treg suppression (70). Within these contact-dependent mechanisms, CTLA-4 is a major mediator of suppression (61,85). Recently, Tregs were also shown to inhibit activation of conventional T cells by mechanisms involving cyclic AMP (cAMP), a known inhibitor of T cell growth, differentiation, and proliferation (reviewed in reference 94).…”

Section: Treg Phenotype and Suppressive Mechanismsmentioning

confidence: 99%

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

Moreno‐Fernandez

Presicce

Chougnet

2012

J Virol

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CTLA‐4 is required by CD4⁺CD25⁺ Treg to control CD4⁺ T‐cell lymphopenia‐induced proliferation

Cited by 88 publications

References 39 publications

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Mesenchymal Stem Cells Protect Breast Cancer Cells through Regulatory T Cells: Role of Mesenchymal Stem Cell-Derived TGF-β

Regulatory T cells inhibit acute IFN-γ synthesis without blocking T-helper cell type 1 (Th1) differentiation via a compartmentalized requirement for IL-10

Homeostasis and Function of Regulatory T Cells in HIV/SIV Infection

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