Expression of Dual TCR on DO11.10 T Cells Allows for Ovalbumin-Induced Oral Tolerance to Prevent T Cell-Mediated Colitis Directed against Unrelated Enteric Bacterial Antigens

Zhou, Pengfei; Borojevic, Rajka; Streutker, Cathy; Snider, Denis P.; Liang, Hong; Croitoru, Kenneth

doi:10.4049/jimmunol.172.3.1515

Cited by 53 publications

(45 citation statements)

References 40 publications

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“…These results provide stronger evidence that suppression is nonspecific. However, this experiment is also not conclusive because the regulatory and effector T cells were obtained from recombinase-sufficient, TCR Tg mice and it is now appreciated that they are not likely to be monospecific because of the expression of endogenous TCR-␣ genes (51,54,55). This likelihood is especially important in the Thornton and Shevach study (19) because the TCR Tg Tregs were obtained from mice expressing different MHC haplotypes.…”

Section: Few If Any Cd4mentioning

confidence: 96%

“…However, the natural Tregs observed in the latter TCR Tg systems are dependent upon the expression of nontransgenic TCR ␣-chains because they are not detected in recombinase-deficient mice (51,54,55). Why TCR75 mice fail to develop significant levels of natural Tregs expressing nontransgenic TCR ␣-chains has not been determined, but this phenomenon is not limited to the TCR75 Tg mice because we have observed a similar pattern in Tg mice expressing the OT2 TCR (our unpublished observations).…”

Section: Few If Any Cd4mentioning

confidence: 99%

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Antigen, in the Presence of TGF-β, Induces Up-Regulation ofFoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses

Kapp

Honjo

Kapp³

et al. 2007

The Journal of Immunology

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CD4+CD25+ regulatory T cells (Tregs) inhibit immune responses to a variety of Ags, but their specificity and mechanism of suppression are controversial. This controversy is largely because many studies focused on natural Tregs with undefined specificities and suppression has frequently been measured on polyclonal T cell responses. To address the issue of specificity further, we have bred Kd-specific, CD4+ TCR (TCR75) transgenic mice to Foxp3gfp knockin reporter mice to permit sorting of Tregs with a known specificity. Foxp3gfp.TCR75 mice did not express significant numbers of natural FoxP3+ Tregs expressing the TCR75 transgenes, but FoxP3 expression was induced by stimulating with Kd plus TGF-β. The resulting GFP+ TCR75 cells were anergic, whereas the GFP− TCR75 cells proliferated upon restimulation with Kd peptide. Yet both exhibited severely reduced expression of intracellular IFN-γ and TNF-α upon restimulation. GFP+, but not GFP−, TCR75 T cells suppressed responses by naive TCR75 T cells and by nontransgenic spleen cells stimulated with anti-CD3. GFP+ TCR75 cells also inhibited polyclonal C57BL/6 anti-Kd CTL responses if the APC expressed Kd and both MHC class I and class II, and responses by OT1 T cells to B6.Kd.OVA but not B6.Kd plus OVA expressing APC, demonstrating linked-suppression of CD8 responses. Thus, Tregs exhibit a greater degree of specificity in vitro than previously appreciated. The observation that Tregs and responder T cells must recognize the same APC provides a mechanistic explanation for the observation that Tregs must be in direct contact with effector T cells to suppress their responses.

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Section: Few If Any Cd4mentioning

confidence: 96%

Section: Few If Any Cd4mentioning

confidence: 99%

Antigen, in the Presence of TGF-β, Induces Up-Regulation ofFoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses

Kapp

Honjo

Kapp³

et al. 2007

The Journal of Immunology

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“…Each animal subgroup contained 8 male mice in the first experiment (total of 32 mice) and 5 in the second independent experimental set. Only male mice were used, similar to prior studies (33).…”

Section: Tolerance Protocolmentioning

confidence: 99%

Enhanced Oral Tolerance in Transgenic Mice with Hepatocyte Secretion of IL-10

Safadi

Álvarez

Ohta

et al. 2005

The Journal of Immunology

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Several cytokines derived from Th3 and Tr1 cells, including IL-10, are believed to regulate oral tolerance, but direct evidence is lacking. We have explored the potential role of IL-10 by generating transgenic (TG) mice with sustained hepatocyte-specific expression of rat IL-10. TG mice expressed rat IL-10 downstream of a transthyretin promoter, which led to serum levels that were increased 10- to 100-fold compared with normal animals. Animals were orally administered 1 mg of whole OVA for 5 consecutive days, with control animals receiving PBS. There were six animal groups: Either OVA or PBS were fed orally to rat IL-10 TG mice, non-TG wild-type mice without IL-10 administration, and non-TG wild-type mice administered rat IL-10 systemically. On day 8, all mice were immunized with two injections of OVA, and then analyzed on day 18. T cell proliferation responses were reduced by 65.8 ± 14.3% after feeding of OVA in rIL-10 TG animals, compared with 39.4 ± 15.6% in the non-TG mice (p = 0.02). Anti-OVA titers were expressed as fold increase over naive non-TG mice. After feeding, titers decreased by ∼33% (from 3- to 2-fold) in TG animals and, to a lesser extent, in non-TG animals. IFN-γ secretion by cultured popliteal lymphocytes decreased in TG animals by 83% after feeding and by 69% in non-TG animals. IL-4 secretion increased 4-fold in TG-fed mice, but did not significantly change in non-TG OVA-fed animals. In contrast to hepatic TG expression of rIL-10, systemic administration of rIL-10 had only a modest effect on tolerance. IL-10, when transgenically expressed in the liver enhances mucosal tolerance to an oral Ag.

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“…Studies utilizing bystander suppression and oral tolerance in murine models of colitis have shown success in ameliorating disease by utilizing foreign antigens like OVA, as well as intrinsic antigens like murine cecal antigen-1 and colonic extracted protein [24,25,26]. OVA-specific Tregs generated ex vivo and injected into the CD45RB hi model of colitis were able to prevent and treat colitis after feeding the mice OVA.…”

Section: In Vivo Approachmentioning

confidence: 99%

Immune Cell Therapy in IBD

Dunkin

Mehandru

Colombel³

2014

Dig Dis

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The therapeutic landscape of IBD has undergone a dramatic transformation since the advent of biologic therapies, especially TNF inhibitors. However, 30% of patients are primary nonresponders to biologic therapy and secondary failures are frequent. Due to substantial progress in our understanding of the biology of regulatory T cells (Tregs) and in the pathways of homing to the gastrointestinal tract, novel cell-based therapies for IBD have become possible. For example, although a reductionist view, one could envisage IBD as an imbalance between the proinflammatory effectors (such as Th17 cells) and the anti-inflammatory regulators (like Tregs). Here we focus on the development of ex vivo and in vivo approaches to enhance Tregs in the gastrointestinal tract. Specifically, herein we highlight a recently concluded phase 1/2a clinical trial that investigated the safety and efficacy of a single injection of escalating doses of autologous ovalbumin-specific Tregs in patients with active Crohn's disease refractory to conventional therapy. This therapy was well tolerated and demonstrated dose-related efficacy. We also discuss the potential of directing Tregs derived through intranasal as well as epicutaneous immunization to the gastrointestinal tract by enhancing their gut homing signature and their potential to decrease gastrointestinal inflammation. Finally, the strengths and pitfalls of these new therapeutic approaches are discussed as we move forward in this largely uncharted territory.

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Expression of Dual TCR on DO11.10 T Cells Allows for Ovalbumin-Induced Oral Tolerance to Prevent T Cell-Mediated Colitis Directed against Unrelated Enteric Bacterial Antigens

Cited by 53 publications

References 40 publications

Antigen, in the Presence of TGF-β, Induces Up-Regulation ofFoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses

Antigen, in the Presence of TGF-β, Induces Up-Regulation ofFoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses

Enhanced Oral Tolerance in Transgenic Mice with Hepatocyte Secretion of IL-10

Immune Cell Therapy in IBD

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