Regulatory T Cells Control Immune Responses through Their Non-Redundant Tissue Specific Features

Lehtimäki, Sari; Lahesmaa, Riitta

doi:10.3389/fimmu.2013.00294

Cited by 33 publications

(23 citation statements)

References 146 publications

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“…In addition to residing in lymphoid tissues, T regs are found in adipose tissue. These cells appear to control immune suppression during starvation and inflammation triggered by obesity and therefore, may contribute to the development of metabolic diseases [116,117]. To maintain Foxp3 expression, adipose tissue-associated T regs require expression of peroxisome proliferator-activated receptor g, a lipid-activated transcription factor [118].…”

Section: Discussionmentioning

confidence: 99%

mTOR and metabolic regulation of conventional and regulatory T cells

Liu

Chapman

Karmaus

et al. 2015

Journal of Leukocyte Biology

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mTOR signaling links bioenergetic and biosynthetic metabolism to immune responses. mTOR is activated by diverse upstream stimuli, including immune signals, growth factors, and nutrients. Recent studies highlight crucial roles of mTOR signaling in immune functions mediated by conventional T cells and T In this review, we discuss the regulation of mTOR signaling in T cells and the functional impacts of mTOR and metabolic pathways on T cell-mediated immune responses, with a particular focus on the differentiation and function of T.

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Section: Discussionmentioning

confidence: 99%

mTOR and metabolic regulation of conventional and regulatory T cells

Liu

Chapman

Karmaus

et al. 2015

Journal of Leukocyte Biology

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“…On the other hand, the dramatic decrease of Treg cells in an obese animal model as well as in atherosclerotic plaques serves as a reminder that there is not one common Treg cell dynamic in health versus disease. For the majority of these tissues, microarray or RNAseq‐based gene‐expression profiling of resident Treg cells is still lacking and the diversity of tissue versus lymphoid‐derived Treg cells has been mainly described only on the basis of increased expression of markers such as cytotoxic T‐lymphocyte antigen 4, CD103, glucocorticoid‐induced tumour necrosis factor receptor family‐related gene, IL‐10, transforming growth factor‐β and a combination of chemokine receptors . Because of the different methods used to purify Treg cells from tissues (single versus double cell sorting, different enzymatic or mechanical tissue digestion protocols) and to perform phenotypic analysis (gene expression profiling, flow cytometry, immunohistochemistry), it is difficult to understand to which extent they share similar features beside a common activated/memory phenotype …”

Section: Regulatory T Cells: Phenotypic and Functional Specializationmentioning

confidence: 99%

Adipose tissue‐resident regulatory T cells: phenotypic specialization, functions and therapeutic potential

Cipolletta

2014

Immunology

107

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Summary Foxp3+ CD4 + regulatory T (Treg) cells, recognized to be one of the most important defences of the human body against an inappropriate immune response, have recently gained attention from those outside immunology thanks to the compelling evidence for their capability to exert non-canonical immune functions in a variety of tissues in health and disease. The recent discovery of the differences between tissue-resident Treg cells and those derived from lymphoid organs is affecting the mindset of many investigators now questioning the broad applicability of observations originally based on peripheral blood/lymphoid organ cells. So far, the best characterized 'Treg flavour' comes from studies focused on their role in suppressing adipose tissue inflammation and obesity-driven insulin resistance. Adipose tissue derived Treg cells are distinct from their counterparts in lymphoid organs based on their transcriptional profile, T-cell receptor repertoire, and cytokine and chemokine receptor expression pattern. These cells are abundant in visceral adipose tissue of lean mice but their number is greatly reduced in insulin-resistant animal models of obesity. Interestingly, peroxisome-proliferator-activated receptor c expression by visceral adipose tissue Treg cells is crucial for their accumulation, phenotype and function in the fat and surprisingly necessary for complete restoration of insulin sensitivity in obese mice by the anti-diabetic drug Pioglitazone. This review surveys recent findings relating to the unique phenotype and function of adipose tissue-resident Treg cells, speculates on the nature of their dynamics in lean and obese mouse models, and analyses their potential therapeutic application in the treatment of type 2 diabetes.

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“…tTregs express a TCR repertoire with a bias for self, being most important in the prevention of autoimmunity, while pTregs are present to moderate response to foreign antigens like those from microbiota or diet, as well as fetus-derived antigens during pregnancy (8). Therefore, the contributions to the immune regulation by both subpopulations are not redundant, and therefore, the participation of both is required to effectively suppress immune response (9,10).…”

Section: Introductionmentioning

confidence: 99%

Large-Scale Generation of Human Allospecific Induced Tregs With Functional Stability for Use in Immunotherapy in Transplantation

et al. 2020

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Regulatory T cells play an important role in the control of autoimmune diseases and maintenance of tolerance. In the context of transplantation, regulatory T cells (Tregs) have been proposed as new therapeutic tools that may induce allospecific tolerance toward the graft, avoiding the side effects induced by generalized immunosuppressors. Although most clinical trials are based on the use of thymic Tregs in adoptive therapy, some reports suggest the potential use of in vitro induced Tregs (iTregs), based on their functional stability under inflammatory conditions, indicating an advantage in a setting of allograft rejection. The aim of this work was to generate and expand large numbers of allospecific Tregs that maintain stable suppressive function in the presence of pro-inflammatory cytokines. Dendritic cells were derived from monocytes isolated from healthy donors and were co-cultured with CTV-labeled naïve T cells from unrelated individuals, in the presence of TGF-β1, IL-2, and retinoic acid. After 7 days of co-culture, proliferating CD4 + CD25 ++ CTV − cells (allospecific iTregs) were sorted and polyclonally expanded for 6 weeks in the presence of TGF-β1, IL-2, and rapamycin. After 6 weeks of polyclonal activation, iTregs were expanded 230,000 times, giving rise to 4,600 million allospecific iTregs. Allospecific iTregs were able to specifically suppress the proliferation of autologous CD4 + and CD8 + T cells in response to the allo-MoDCs used for iTreg generation, but not to third-party allo-MoDCs. Importantly, 88.5% of the expanded cells were CD4 + CD25 + FOXP3 + , expressed high levels of CCR4 and CXCR3, and maintained their phenotype and suppressive function in the presence of TNF-α and IL-6. Finally, analysis of the methylation status of the FOXP3 TSDR locus demonstrated a 40% demethylation in the purified allospecific iTreg, prior to the polyclonal expansion. Interestingly, the phenotype and suppressive activity of expanded allospecific iTregs were maintained after 6 weeks of expansion, despite an increase in the methylation status of the FOXP3 TSDR. In conclusion, this is the first report that demonstrates a large-scale generation of allospecific iTregs that preserve a stable phenotype and suppressor function in the presence of pro-inflammatory cytokines and pave the way for adoptive cell therapy with iTregs in transplanted patients.

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Regulatory T Cells Control Immune Responses through Their Non-Redundant Tissue Specific Features

Cited by 33 publications

References 146 publications

mTOR and metabolic regulation of conventional and regulatory T cells

mTOR and metabolic regulation of conventional and regulatory T cells

Adipose tissue‐resident regulatory T cells: phenotypic specialization, functions and therapeutic potential

Large-Scale Generation of Human Allospecific Induced Tregs With Functional Stability for Use in Immunotherapy in Transplantation

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