T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space?

Bernardo, David; Al-Hassi, Hafid O.; Mann, Elizabeth R.; Tee, Cheng T.; Murugananthan, Aravinth; Peake, S.; Hart, Ailsa; Knight, Stella C.

doi:10.1016/j.humimm.2011.12.017

Cited by 14 publications

(7 citation statements)

References 38 publications

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“…While the important role of thymically committed, natural CD4 + Treg cells in peripheral immune tolerance has been well established, certain immunoregulatory molecules can also be induced in developing effector T cells, including Foxp3 and IL‐10 , thus allowing negative feedback inhibition of T‐cell responses. This study demonstrates that CD39, a B‐cell‐associated molecule previously shown to be critical in natural Foxp3 + Treg cell function , is readily induced on CD8 + T cells by pro‐inflammatory cytokines and mediates potent suppressive activity.…”

Section: Discussionmentioning

confidence: 99%

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells

et al. 2016

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Immune responses to protein antigens involve CD4+ and CD8+ T cells, which follow distinct programs of differentiation. Naïve CD8 T cells rapidly develop cytotoxic T‐cell (CTL) activity after T‐cell receptor stimulation, and we have previously shown that this is accompanied by suppressive activity in the presence of specific cytokines, i.e. IL‐12 and IL‐4. Cytokine‐induced CD8+ regulatory T (Treg) cells are one of several Treg‐cell phenotypes and are Foxp3− IL‐10+ with contact‐dependent suppressive capacity. Here, we show they also express high level CD39, an ecto‐nucleotidase that degrades extracellular ATP, and this contributes to their suppressive activity. CD39 expression was found to be upregulated on CD8+ T cells during peripheral tolerance induction in vivo, accompanied by release of IL‐12 and IL‐10. CD39 was also upregulated during respiratory tolerance induction to inhaled allergen and on tumor‐infiltrating CD8+ T cells. Production of IL‐10 and expression of CD39 by CD8+ T cells was independently regulated, being respectively blocked by extracellular ATP and enhanced by an A2A adenosine receptor agonist. Our results suggest that any CTL can develop suppressive activity when exposed to specific cytokines in the absence of alarmins. Thus negative feedback controls CTL expansion under regulation from both nucleotide and cytokine environment within tissues.

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Section: Discussionmentioning

confidence: 99%

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells

et al. 2016

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“…We are aware that we did not study the capacity of RA-MoDC to induce regulatory T cells. That is because our recent evidence has shown that forkhead box protein 3 (FoxP3) expression may not be a valid marker to identify T cells with a regulatory phenotype; because its expression is dynamic, dependent upon T cell densities, it is subsequently lost in time following removal of the stimulant, and FoxP3 + T cells developed in vitro do not perform a suppressive activity [36]. However, we have shown that RA-MoDC displayed a decreased stimulatory capacity in a dose-dependent fashion (Fig.…”

Section: Discussionmentioning

confidence: 99%

Lost therapeutic potential of monocyte-derived dendritic cells through lost tissue homing: stable restoration of gut specificity with retinoic acid

Bernardo

Mann

Al-Hassi

et al. 2013

Clinical and Experimental Immunology

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SummaryHuman monocyte-derived dendritic cells (DC) (MoDC) are utilized for immunotherapy. However, in-vitro immunological effects are often not mirrored in vivo. We studied the tissue-homing potential of MoDC. Circulating monocytes and DC expressed different tissue-homing markers and, during in-vitro development of MoDC, homing marker expression was lost resulting in a ‘homeless’ phenotype. Retinoic acid (RA) induced gut-homing markers (β7 and CCR9) and a regulatory phenotype and function [decreased human leucocyte antigen D-related (HLA-DR) and increased ILT3 and fluorescein isothiocyanate (FITC-dextran uptake) in MoDC]. RA-MoDC were less stimulatory and primed conditioned T cells with a gut-homing profile (β7+CLA−). Unlike the normal intestinal microenvironment, that from inflamed colon of ulcerative colitis (UC) patients did not induce regulatory properties in MoDC. However, RA-MoDC maintained their regulatory gut-specific properties even in the presence of UC microenvironment. Therefore, MoDC may be ineffectual for immunotherapy because they lack tissue-homing and tissue-imprinting specificity. However, MoDC rehabilitation with gut-homing potential by RA could be useful in promoting immunotherapy in pathologies such as UC.

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“…In order to evaluate the functional consequences of RA-induced expression on CD4+ cells, DCs and autologous or allogeneic T cells (CD14-depleted PBMCs) were co-cultured in a 1:10 ratio (DC:T cell) [22]. At day 5 of DC differentiation, T cells were added and incubated for another 5 days.…”

Section: Methodsmentioning

confidence: 99%

The Mucosal Factors Retinoic Acid and TGF-β1 Induce Phenotypically and Functionally Distinct Dendritic Cell Types

Hartog

Altena

Savelkoul

et al. 2013

Int Arch Allergy Immunol

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Non-inflammatory dendritic cell (DC) subsets play an essential role in preventing massive inflammation in mucosal tissues. We investigated whether mucosa-related factors, namely retinoic acid (RA) and transforming growth factor-β (TGF-β1), can induce such DC types. DCs were differentiated from monocytes in the absence or presence TGF-β1 and RA. The phenotype as well as responsiveness to bacterial ligands was studied in detail. Compared to monocyte-derived DCs (moDCs), the expression of co-stimulatory molecule CD86 and DC maturation marker CD83 were strongly reduced by RA and TGF-β1. In addition, both RA- and TGF-β1-induced DCs showed strongly decreased responsiveness to stimulation with the bacterial ligands lipopolysaccharide and peptidoglycan, and produced significantly lower levels of the pro-inflammatory cytokines IL-12 and TNF-α compared to moDCs, whilst IL-10 production was not significantly reduced. DCs differentiated under the influence of RA uniquely expressed markers related to intestinal homing (CD103 and integrin β7). In addition, CCR7, which mediates homing to lymph nodes, was expressed by DCs differentiated in the presence of RA, and also to a lesser extent by the other DC types. Furthermore, whereas moDCs and TGF-β1-derived moDCs expressed high levels of CD32, RA-derived DCs lacked CD32 expression but expressed high levels of CD64, suggesting that RA-DCs may primarily respond to soluble proteins and moDCs, and TGF-β DCs to immune complexes. The data presented here support the hypothesis that the mucosal factors TGF-β1 and RA, which can also be provided through dietary intake of dairy products, result in functionally and phenotypically distinct DC types with non-inflammatory properties.

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T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space?

Cited by 14 publications

References 38 publications

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells

Lost therapeutic potential of monocyte-derived dendritic cells through lost tissue homing: stable restoration of gut specificity with retinoic acid

The Mucosal Factors Retinoic Acid and TGF-β1 Induce Phenotypically and Functionally Distinct Dendritic Cell Types

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T-cell proliferation and forkhead box P3 expression in human T cells are dependent on T-cell density: physics of a confined space?

Cited by 14 publications

References 38 publications

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8+ T cells

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8+ T cells

Lost therapeutic potential of monocyte-derived dendritic cells through lost tissue homing: stable restoration of gut specificity with retinoic acid

The Mucosal Factors Retinoic Acid and TGF-β1 Induce Phenotypically and Functionally Distinct Dendritic Cell Types

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IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells

IL‐12 and IL‐4 activate a CD39‐dependent intrinsic peripheral tolerance mechanism in CD8⁺ T cells