Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells

Veeken, Joris van der; Campbell, Clarissa; Pritykin, Yuri; Schizas, Michail; Verter, Jacob; Hu, Wei; Wang, Zhong-Min; Matheis, Fanny; Mucida, Daniel; Charbonnier, Louis-Marie; Chatila, Talal; Rudensky, Alexander Y.

doi:10.1016/j.immuni.2022.05.010

Cited by 45 publications

(33 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Van der Veeken et al. ( 5 ) reported a peripheral Treg transcriptional program which is induced by events in the intestine and is independent of FoxP3. Hong et al.…”

Section: Mechanisms Of Inflammation Resolution Via ...mentioning

confidence: 99%

“…Recent studies exploring oral agents that modulate peripheral inflammation via the small intestinal axis ( 4 , 5 ) have provided unexpected insights that bridge the fields of oral tolerance, mucosal immunity, and the gut microbiome. This raises the possibility of medicines which induce resolution of systemic inflammation using mechanisms similar to those essential to prevent inflammatory responses to the high burden of daily exposure to food antigens in the proximal small intestine ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Harnessing the small intestinal axis to resolve systemic inflammation

Bodmer¹,

Itano²,

McInnes

2022

Front. Immunol.

View full text Add to dashboard Cite

This Perspective presents the potential of the Small Intestinal Axis, a sub-division of the Gut-immune Axis, to modulate systemic inflammation based on sensing contents of the gut lumen. Gut mucosal immunity regulates tolerance to food and gut contents and is a significant factor in maintaining systemic homeostasis without compromising immunity to pathogens. This is achieved through anatomical structures and signaling pathways that link the tolerogenic potential of the proximal small intestine to systemic immunity. Non-live preparations of microbes isolated from human small intestinal mucosa, and the extracellular vesicles (EVs) which they shed, can resolve systemic inflammation without systemic exposure after oral delivery. The mechanism involves primary interactions with pattern recognition receptors followed by trafficking of immune cells through mesenteric lymph nodes. This generates in the periphery a population of circulating CD4+ T cells which have regulatory function but an atypical FoxP3- phenotype. There is no modification of the resident gut microbiome. Discoveries using this novel approach of targeting mucosal microbial elements to the tolerogenic proximal regions of the small intestine are revealing some of the mysteries of the relationship between the gut and immune system.

show abstract

“…Van der Veeken et al. ( 5 ) reported a peripheral Treg transcriptional program which is induced by events in the intestine and is independent of FoxP3. Hong et al.…”

Section: Mechanisms Of Inflammation Resolution Via ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Harnessing the small intestinal axis to resolve systemic inflammation

Bodmer¹,

Itano²,

McInnes

2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…Similarly, insertion of a promoter between the TSDR and the start codon of FOXP3 to override the intrinsic regulatory elements and force constitutive expression of endogenous Foxp3 resulted in maintenance of a suppressive phenotype and function [ 110 ]. Relatedly, the ablation of Foxp3 did not eliminate all mouse gut Treg suppressive function [ 111 ], and Foxp3‐deficient pTreg cells retained the ability to inhibit expansion of colonic CD4 + and CD8 + T cells, though not to mediate the suppression of IL‐17 differentiation, mast cell expansion, and the progression of colitis [ 112 ]. Taken together, these studies indicate that additional mechanisms beyond Foxp3 expression are essential for the development of functionally suppressive Treg cells, further supporting approaches to utilize pre‐existing Treg cells.…”

Section: Introductionmentioning

confidence: 99%

“…In the intestine, there is evidence that Treg cells have a tissue‐specific TCR repertoire that differs from effector cells and from Treg cells at other sites [ 177 ], consistent with the idea that local factors shape Treg cell populations and that the origin and selection of TCR may be critical for success. In the gut specifically, key aspects promoting TCR specificities include food antigens and the microbiota [ 112 , 178 ]. Indeed, the microbiome is a key contributor to the development of TCR specificities in the intestine as the tolerogenic balance between commensal and pathogenic species develops [ 177 , 179 ].…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cells as a therapeutic approach for inflammatory bowel disease

Lauková

Zaretsky

2023

Eur J Immunol

View full text Add to dashboard Cite

Foxp3 + T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.

show abstract

“…However, the underlying pathogenesis of UC is too elusive and there is no generally effective therapy for UC. Immune system dysfunction, particularly the imbalance between T-helper 17 (Th17) and regulatory T cells (Treg), is an important event in the occurrence and development of UC. − Th17 cells are characterized by the expression of transcription factor retinoid-related orphan receptor (ROR)γt, secrete cytokine IL-17, and recruit neutrophils as well as macrophages to produce proinflammatory cytokines. − In contrast, Treg cells are featured by the transcription factor Forkhead box P3 (Foxp3), which maintain immunosuppressive and immune tolerance through secreting IL-10. − As for UC patients, the proportion of Treg cells in peripheral blood and colonic mucosa is sharply reduced . However, the proportion of Th17 cells and the level of IL-17A demonstrate an increasing trend, and the clinical symptom of mice with dextran sulfate sodium (DSS)-induced colitis is improved upon the knockdown of IL-17A. − Collectively, restoring Th17/Treg balance may be an effective strategy for the treatment of UC.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Sesquiterpene Lactone Derivatives as Potent PKM2 Activators for the Treatment of Ulcerative Colitis

et al. 2023

View full text Add to dashboard Cite

The pyruvate kinase M2 (PKM2) can significantly affect the differentiation of Th17 and Treg cells; thus, it is considered a promising target for UC therapy. Herein, five series of costunolide (Cos) derivatives are designed, synthesized, and biologically evaluated. Among them, D5 exhibits excellent immunomodulatory activity against T-cell proliferation and potent PKM2 activating activity. Meanwhile, it has been confirmed that D5 can also covalently interact with Cys424 of PKM2. The molecular docking and molecular dynamic (MD) studies indicate that difluorocyclopropyl derivative of D5 improves the protein–ligand interaction by interacting with Arg399 electrostatically. Furthermore, D5 significantly dampens the differentiation of Th17 but not Treg cells to recover the Th17/Treg balance, which is attributed to the suppression of PKM2-mediated glycolysis. Oral administration of D5 ameliorates the symptoms of dextran sulfate sodium (DSS)- and 2,4,6-trinitro-benzenesulfonic acid (TNBS)-induced colitis in mouse model. Collectively, D5 has the potential to be developed as a novel anti-UC candidate.

show abstract

Genetic tracing reveals transcription factor Foxp3-dependent and Foxp3-independent functionality of peripherally induced Treg cells

Cited by 45 publications

References 67 publications

Harnessing the small intestinal axis to resolve systemic inflammation

Harnessing the small intestinal axis to resolve systemic inflammation

Regulatory T cells as a therapeutic approach for inflammatory bowel disease

Discovery of Novel Sesquiterpene Lactone Derivatives as Potent PKM2 Activators for the Treatment of Ulcerative Colitis

Contact Info

Product

Resources

About