Oral Tolerance and TGF-&amp;#946; -Producing Cells

Faria, Ana Maria Caetano; Weiner, Howard L.

doi:10.2174/187152806778256034

Cited by 100 publications

(62 citation statements)

References 169 publications

(261 reference statements)

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“…After TCR cross-linking a lamina propria T cell is weakly proliferative and secretes 5-to 10-fold less cytokine than its effector/memory circulating equivalent (54,55). This mucosal phenotype is particularly intriguing in that a Th3 cell, which secretes TGF-␤, has been proposed to regulate oral tolerance (56) and chronic intestinal inflammation (39,57). In addition, we have previously reported that engagement of different members of the ␤ 1 integrin family modulates either TCR-induced proliferation or activation induced cell death (25).…”

Section: Discussionmentioning

confidence: 99%

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

Das¹,

Levine

2008

The Journal of Immunology

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TGF-β signaling is critical for controlling naive T cell homeostasis and differentiation; however, the biological and biochemical changes induced by TGF-β in effector/memory T cells are poorly defined. We show that although TGF-β inhibits effector/memory peripheral blood T lymphoblast proliferation and IL-2 production, the intensity and kinetics for TCR-induced global tyrosine phosphorylation are markedly increased compared with that in untreated cells or naive T cells. After TCR ligation, tyrosine phosphorylation of proximal tyrosine kinases and docking proteins like linker for activation of T cells is maintained for >30 min in TGF-β-primed cells compared with untreated cells where phosphorylation of these targets returned to basal levels by 10 min. Extended phosphorylation of linker for activation of T cells in treated peripheral blood T selectively prolongs ERK 1/2 signaling and phospholipase C-γ1 activation leading to increased Ca2+ flux. A kinase/phosphatase imbalance could not account for extended phosphorylation as CD45R, SHP-1, and SHP-2 expression remains unaltered. The contradiction between prolonged signal transduction and inhibition of proliferation is partially explained by the observation that TGF-β priming results in ERK 1/2-independent p21 induction and decreased cyclin D1 expression leading to accumulation of T cells in G0/G1 phases of the cell cycle and cell cycle arrest. Despite inhibition of T cell function by TGF-β priming, TCR and cytokine signaling pathways are intact and selectively extended, suggesting that suppression in the effector/memory T cell is mediated by reprogramming signal transduction, rather than its inhibition as in the naive T cell.

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Section: Discussionmentioning

confidence: 99%

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

Das¹,

Levine

2008

The Journal of Immunology

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“…This was surprising since TGF-β was considered a potent regulatory cytokine with inhibitory effects on T cell differentiation [46]. Indeed, TGF-β, which is produced by regulatory T cells (T-reg) [47,48] and cells of the innate immune system [46], induces Foxp3, a transcription factor that has been associated with the generation of T-reg cells [49]. We and other have shown that addition of TGF-β to Foxp3 − T cells can lead to Foxp3 + T cells with regulatory activities [17,50].…”

Section: Reciprocal Relationship Between Th17 and Induced T-reg (It-reg)mentioning

confidence: 99%

Th17: the third member of the effector T cell trilogy

Bettelli

Korn

Kuchroo

2007

Current Opinion in Immunology

557

437

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T helper responses have now grown to include three T cell subsets: Th1, Th2 and Th17. Th17 cells have recently emerged as a third independent T cell subset which may play an essential role in protection against certain extracellular pathogens. However, Th17 cells with specificity for self antigens are highly pathogenic and lead to the development of inflammation and severe autoimmunity. A combination of TGF-β plus IL-6 and the transcription factors STAT3 and RORγt were recently described to be essential for initial differentiation of Th17 cells, and IL-23 for the later stabilization of the Th17 cell subset. Here we introduce another player IL-21, which is produced by Th17 themselves, plays an important role in the amplification of Th17 cells. Thus Th17 cells may undergo three distinct steps of development: differentiation, amplification and stabilization in which distinct cytokine play a role.

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“…Differences between antigen-gavaged and saline-gavaged TS mice. 4 TR mice saline-gavaged. 5 TR mice antigen-gavaged.…”

Section: Feeding Ova For 30 Consecutive Days Did Not Inhibit the Igg mentioning

confidence: 99%

“…Kamphorst, 3 Elize A. Hayashi, 4 Maria Bellio, 4 Claudia R. Carvalho, 3 Ana M. C. Faria, 3 Kátia C. C.…”

Section: Introductionmentioning

confidence: 99%

Innate profiles of cytokines implicated on oral tolerance correlate with low‐ or high‐suppression of humoral response

et al. 2010

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Summary Oral tolerance (OT) is being studied with great interest because of its therapeutic potential in allergy and autoimmunity. In the present study, two mouse strains with extreme phenotypes of OT susceptibility (TS) or resistance (TR) to ovalbumin (OVA) were used to demonstrate whether the tr and ts genes, cumulated during 18 generations of bi‐directional genetic selection, influence expression of immunobiological traits in naive or antigen‐gavaged TR/TS mice. The difference in anti‐OVA titres was 2048‐fold between OVA‐gavaged TS and TR mice. Tolerance susceptibility to OVA gavage in individuals from a (TS × TR)F2 population was 24% high‐susceptibility, 62% low‐susceptibility and 14% non‐tolerant. Different antigens, unrelated to OVA, were tested by gavage and TS mice were generally susceptible while TR mice were resistant. The stability of TS and TR phenotypes was not affected by the use of strict protocols of intraperitoneal immunization or feeding over 30 consecutive days. The levels of interleukin‐2 (IL‐2), IL‐4, interferon‐γ and IL‐10 cytokines evaluated in concanavalin A‐stimulated spleen cells from naive mice and in OVA‐stimulated spleen cells from OVA‐gavaged mice were higher in TS mice. Interleukin‐10 was up‐regulated in OVA‐gavaged TS mice and down‐regulated in TR mice. In naive mice, the percentage of CD4+ CD25+ and CD4+ Foxp3+ spleen cells and IL‐10 expression by CD4+ cells was significantly higher in TS mice. These results indicate that regulation of IL‐10 expression could be an important factor contributing to the mechanisms controlling OT susceptibility, and that the OT responses of TR and TS individuals strongly correlate with their innate potential to secrete this cytokine.

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Oral Tolerance and TGF-β -Producing Cells

Cited by 100 publications

References 169 publications

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

TGF-β Inhibits IL-2 Production and Promotes Cell Cycle Arrest in TCR-Activated Effector/Memory T Cells in the Presence of Sustained TCR Signal Transduction

Th17: the third member of the effector T cell trilogy

Innate profiles of cytokines implicated on oral tolerance correlate with low‐ or high‐suppression of humoral response

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