12 results on '"Levings, Megan K."'
Search Results
2. Functional dynamics of naturally occurring regulatory T cells in health and autoimmunity.
- Author
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Levings MK, Allan S, d'Hennezel E, and Piccirillo CA
- Subjects
- Animals, Humans, Inflammation immunology, Autoimmunity immunology, T-Lymphocytes, Regulatory immunology
- Abstract
A network of regulatory T (Treg) cells exists to downregulate immune responses in various inflammatory circumstances and ultimately assure peripheral T cell tolerance. Naturally occurring CD4(+)CD25(+) Treg cell represents a major lymphocyte population engaged in the dominant control of self-reactive T responses and maintenance of tolerance within this network. CD4(+)CD25(+) Treg cells differentiate in the normal thymus as a functionally distinct subpopulation of T cells bearing a broad T cell receptor repertoire endowing these cells with the capacity to recognize a wide spectrum of self-Ag and non-self-Ag specificities. The development of CD4(+)CD25(+) Treg cells is genetically determined, influenced by Ag-specific and nonspecific signals, costimulation, and cytokines that control their activation, expansion, and suppressive activity. Functional abrogation of these cells in vivo, or genetic defects that affect their development or function, unequivocally predisposes animals and humans to the onset of autoimmune and other inflammatory diseases. Studies have shed light in our understanding of the cellular and molecular basis of CD4(+)CD25(+) Treg cell-mediated immune regulation. In this chapter, we discuss the contribution of naturally occurring CD4(+)CD25(+) Treg cells in the induction of immunologic self-tolerance in animal models and humans and attempt to provide a comprehensive overview of recent findings regarding the phenotype, functional dynamics, and effector mechanism of these cells in autoimmune diseases.
- Published
- 2006
- Full Text
- View/download PDF
3. Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities.
- Author
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Halvorson, Torin, Tuomela, Karoliina, and Levings, Megan K.
- Subjects
REGULATORY T cells ,CELL metabolism ,AUTOIMMUNE diseases ,IMMUNOSUPPRESSION ,GENOME editing ,DRUG therapy - Abstract
Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti‐tumor immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example, through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody‐mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function. Mounting evidence has shown that targeting metabolic pathways can selectively promote or inhibit Treg function. This review aims to synthesize the current understanding of Treg metabolism and discuss emerging metabolic targeting strategies in the contexts of transplantation, autoimmunity, and cancer. We discuss approaches to gene editing and cell culture to manipulate Treg metabolism during ex vivo expansion for ACT, as well as in vivo nutritional and pharmacological interventions to modulate Treg metabolism in disease states. Overall, the intricate connection between metabolism and phenotype presents a powerful opportunity to therapeutically tune Treg function. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. The parasite cytokine mimic Hp‐TGM potently replicates the regulatory effects of TGF‐β on murine CD4+ T cells.
- Author
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White, Madeleine P J, Smyth, Danielle J, Cook, Laura, Ziegler, Steven F, Levings, Megan K, and Maizels, Rick M
- Subjects
REGULATORY T cells ,CYTOKINES ,T cells ,HOMEOSTASIS ,GENE expression profiling ,IMMUNE system ,INTERLEUKIN-7 - Abstract
Transforming growth factor‐beta (TGF‐β) family proteins mediate many vital biological functions in growth, development and regulation of the immune system. TGF‐β itself controls immune homeostasis and inflammation, including conversion of naïve CD4+ T cells into Foxp3+ regulatory T cells (Tregs) in the presence of interleukin‐2 and T‐cell receptor ligands. The helminth parasite Heligmosomoides polygyrus exploits this pathway through a structurally novel TGF‐β mimic (Hp‐TGM), which binds to mammalian TGF‐β receptors and induces Tregs. Here, we performed detailed comparisons of Hp‐TGM with mammalian TGF‐β. Compared with TGF‐β, Hp‐TGM induced greater numbers of Foxp3+ Tregs (iTregs), with more intense Foxp3 expression. Both ligands upregulated Treg functional markers CD73, CD103 and programmed death‐ligand 1, but Hp‐TGM induced significantly higher CD39 expression than did TGF‐β. Interestingly, in contrast to canonical TGF‐β signaling through Smad2/3, Hp‐TGM stimulation was slower and more sustained. Gene expression profiles induced by TGF‐β and Hp‐TGM were remarkably similar, and both types of iTregs suppressed T‐cell responses in vitro and experimental autoimmune encephalomyelitis‐driven inflammation in vivo. In vitro, both types of iTregs were equally stable under inflammatory conditions, but Hp‐TGM‐induced iTregs were more stable in vivo during dextran sodium sulfate‐induced colitis, with greater retention of Foxp3 expression and lower conversion to a ROR‐γt+ phenotype. Altogether, results from this study suggest that the parasite cytokine mimic, Hp‐TGM, may deliver a qualitatively different signal to CD4+ T cells with downstream consequences for the long‐term stability of iTregs. These data highlight the potential of Hp‐TGM as a new modulator of T‐cell responses in vitro and in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
5. Engineered Tolerance: Tailoring Development, Function, and Antigen-Specificity of Regulatory T Cells.
- Author
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Dawson, Nicholas A. J., Vent-Schmidt, Jens, and Levings, Megan K.
- Subjects
TISSUE engineering ,T cells ,IMMUNE response - Abstract
Regulatory T cells (Tregs) are potent suppressors of immune responses and are currently being clinically tested for their potential to stop or control undesired immune responses in autoimmunity, hematopoietic stem cell transplantation, and solid organ transplantation. Current clinical approaches aim to boost Tregs in vivo either by using Treg-promoting small molecules/proteins and/or by adoptive transfer of expanded Tregs. However, the applicability of Treg-based immunotherapies continues to be hindered by technical limitations related to cell isolation and expansion of a pure, well-characterized, and targeted Treg product. Efforts to overcome these limitations and improve Treg-directed therapies are now under intense investigation in animal models and pre-clinical studies. Here, we review cell and protein engineering-based approaches that aim to target different aspects of Treg biology including modulation of IL-2 signaling or FOXP3 expression, and targeted antigen-specificity using transgenic T cell receptors or chimeric antigen receptors. With the world-wide interest in engineered T cell therapy, these exciting new approaches have the potential to be rapidly implemented and developed into therapies that can effectively fine-tune immune tolerance. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
6. TH17 cells in autoimmunity and immunodeficiency: protective or pathogenic?
- Author
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Marwaha, Ashish K., Leung, Nicole J., McMurchy, Alicia N., Levings, Megan K., Bacchetta, Rosa, and Annunziato, Francesco
- Subjects
INTERLEUKIN-17 ,T helper cells ,AUTOIMMUNE diseases ,IMMUNODEFICIENCY ,BACTERIAL diseases ,CROHN'S disease - Abstract
In 2005 a newly discovered T helper cell subset that secreted interleukin (IL)-17 became the center of attention in immunology. Initial studies painted Th17 cells as the culprit for destruction in many different autoimmune and auto-inflammatory diseases. Subsequently, the discovery of patients with primary immunodeficiencies in the IL-17 pathway taught us that Th17 cells have a critical role in defense against certain fungal and bacterial infections. Moreover, the paradoxical exacerbation of Crohn's disease in the clinical trials of a Secukinumab (AIN457), a fully human neutralizing antibody to IL-17A, has cast into doubt a universal pro-inflammatory and harmful role for Th17 cells. Evidence now suggests that depending on the environment Th17 cells can alter their differentiation program, ultimately giving rise to either protective or pro-inflammatory cells. In this review we will summarize the evidence from patients with immunodeficiencies, autoimmune, or auto-inflammatory diseases that teaches us how the pro-inflammatory versus protective function of Th17 cells varies within the context of different human diseases. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
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7. Point mutants of forkhead box P3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked have diverse abilities to reprogram T cells into regulatory T cells.
- Author
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McMurchy, Alicia N., Gillies, Jana, Allan, Sarah E., Passerini, Laura, Gambineri, Eleonora, Roncarolo, Maria Grazia, Bacchetta, Rosa, and Levings, Megan K.
- Subjects
GENETIC mutation ,FORKHEAD transcription factors ,INTESTINAL diseases ,T cells ,IMMUNE response ,IMMUNOLOGIC diseases ,IMMUNODEFICIENCY ,TRANSCRIPTION factors - Abstract
Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a primary immunodeficiency with autoimmunity caused by mutations in forkhead box P3 (FOXP3), which encodes a transcription factor involved in regulatory T (Treg) cell function. The mechanistic basis for how different mutations in FOXP3 cause distinct manifestations of IPEX remains unclear. Objective: To determine whether 3 different point mutants of FOXP3 that cause severe or mild IPEX differ in their ability to reprogram conventional T cells into Treg cells. Methods: Human CD4
+ T cells were transduced with wild-type or point mutant forms of FOXP3, and changes in cell surface marker expression, cytokine production, proliferation and suppressive capacity were assessed. Ex vivo TH 17 cells were also transduced with different forms of FOXP3 to monitor changes in IL-17 production. Results: The forkhead mutant F373A failed to upregulate CD25 and CCR4, did not suppress cytokine production, and induced suppressive activity less effectively than wild-type FOXP3. In contrast, although the forkhead mutant R347H was also defective in upregulation of CD25, it suppressed the production of cytokines, conferred suppressive capacity on CD4+ T cells, and suppressed IL-17 production. F324L, a mutant outside the forkhead domain associated with mild IPEX, was equivalent to wild-type FOXP3 in all aspects tested. Conclusion: Mutations in FOXP3 that cause IPEX do not uniformly abrogate the ability of FOXP3 to regulate transcription and drive the development of Treg cells. These data support the notion that factors in addition to functional changes in Treg cells, such as alterations in conventional T cells, are involved in the pathogenesis of IPEX. [ABSTRACT FROM AUTHOR]- Published
- 2010
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- View/download PDF
8. CD4+ T-regulatory cells: toward therapy for human diseases.
- Author
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Allan, Sarah E., Broady, Raewyn, Gregori, Silvia, Himmel, Megan E., Locke, Natasha, Roncarolo, Maria Grazia, Bacchetta, Rosa, and Levings, Megan K.
- Subjects
T cells ,AUTOIMMUNITY ,ALLERGIES ,GRAFT rejection ,TRANSPLANTATION immunology ,INTERLEUKIN-10 - Abstract
T-regulatory cells (Tregs) have a fundamental role in the establishment and maintenance of peripheral tolerance. There is now compelling evidence that deficits in the numbers and/or function of different types of Tregs can lead to autoimmunity, allergy, and graft rejection, whereas an over-abundance of Tregs can inhibit anti-tumor and anti-pathogen immunity. Experimental models in mice have demonstrated that manipulating the numbers and/or function of Tregs can decrease pathology in a wide range of contexts, including transplantation, autoimmunity, and cancer, and it is widely assumed that similar approaches will be possible in humans. Research into how Tregs can be manipulated therapeutically in humans is most advanced for two main types of CD4
+ Tregs: forkhead box protein 3 (FOXP3)+ Tregs and interleukin-10-producing type 1 Tregs (Tr1 cells). The aim of this review is to highlight current information on the characteristics of human FOXP3+ Tregs and Tr1 cells that make them an attractive therapeutic target. We discuss the progress and limitations that must be overcome to develop methods to enhance Tregs in vivo, expand or induce them in vitro for adoptive transfer, and/or inhibit their function in vivo. Although many technical and theoretical challenges remain, the next decade will see the first clinical trials testing whether Treg-based therapies are effective in humans. [ABSTRACT FROM AUTHOR]- Published
- 2008
- Full Text
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9. Building a CAR-Treg: Going from the basic to the luxury model.
- Author
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Rosado-Sánchez, Isaac and Levings, Megan K.
- Subjects
- *
HEMATOPOIETIC stem cell transplantation , *STEM cell transplantation , *SUPPRESSOR cells , *CHIMERIC antigen receptors , *CELLULAR therapy - Abstract
• Advances in use of chimeric antigen receptors (CARs) in Tregs are reviewed. • Factors to consider when creating CAR-Tregs are discussed. • How progress in CAR-T cell design can be applied to Tregs is discussed. Regulatory T cells (Tregs) control immune homeostasis and prevent exacerbated immune responses, and can be used as cell therapy to dampen a variety of autoimmune or autoinflammatory responses. Treg therapy is significantly more effective if the cells are antigen-specific. One way to re-direct the specificity of Tregs is to engineer them to express a Chimeric Antigen Receptor (CAR). Proof-of-concept studies have shown the potential for "basic" models of CAR-Tregs to be used as cellular therapy in autoimmunity, organ transplantation and hematopoietic stem cell transplantation. In parallel, work in the context of cancer has significantly advanced knowledge of how to optimise CAR-T cell structure and function for more precise and potent function. In this review, we summarize the current state of knowledge about important considerations when generating CAR-Tregs. We also extrapolate from emerging findings with CAR-T cells about strategies to further improve CAR-Treg function, creating "luxury" models with refined activity. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
10. The role of FOXP3 in autoimmunity.
- Author
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Pesenacker, Anne M, Cook, Laura, and Levings, Megan K
- Subjects
- *
SCURFIN (Protein) , *TYPE 1 diabetes , *AUTOIMMUNITY , *TRANSCRIPTION factors , *CELLULAR therapy - Abstract
FOXP3 controls the development and function of T regulatory cells (Tregs). Autoimmunity is linked to changes in FOXP3 activity that can occur at multiple levels and lead to Treg dysfunction. For example, changes in IL-2 signaling, FOXP3 transcription and/or post-translational modifications can all contribute to loss of self-tolerance. As additional pathways of FOXP3 regulation are elucidated, new therapeutic approaches to increase Treg activity either by cell therapy or pharmacological intervention are being tested. Early success from pioneering studies of Treg-based therapy in transplantation has promoted the undertaking of similar studies in autoimmunity, with emerging evidence for the effectiveness of these approaches, particularly in the context of type 1 diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
11. Biomarker-guided stratification of autoimmune patients for biologic therapy.
- Author
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Ivison, Sabine, Des Rosiers, Christine, Lesage, Sylvie, Rioux, John D, and Levings, Megan K
- Subjects
- *
AUTOIMMUNITY , *ETIOLOGY of diseases , *HOMEOSTASIS , *BIOMARKERS , *BIOTHERAPY - Abstract
Autoimmunity results from an intersection of genetic and environmental factors that cause patient-specific perturbations in immune homeostasis. Defining autoimmunity-associated genetic factors has led to mechanistic insight into underlying etiologies, and the development of many biologic therapies that target the immune system. However, biomarker-informed pairing of patients with optimal biologic therapy is lacking. Here, we discuss platforms commonly used to find biomarkers that predict response to biologic therapy in autoimmunity and highlight recent biomarker discoveries. We also outline how the lack of assay standardization is a barrier to successful biomarker validation. Finally, we argue that the successful development of companion biomarkers for biologic therapy requires collaborative approaches that integrate multiple platforms and enable comprehensive measurement of multiple immune pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
12. Defective regulatory and effector T cell functions in patients with FOXP3 mutations.
- Author
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Bacchetta, Rosa, Passerini, Laura, Gambineri, Eleonora, Minyue Dai, Allan, Sarah E., Perroni, Lucia, Dagna-Bricarelli, Franca, Sartirana, Claudia, Matthes-Martin, Susanne, Lawitschka, Anita, Azzari, Chiara, Ziegler, Steven F., Levings, Megan K., Roncarolo, Maria Grazia, and Dai, Minyue
- Subjects
- *
IMMUNOLOGIC diseases , *T cells , *GENETIC mutation , *AUTOIMMUNITY , *INTESTINAL diseases , *PHENOTYPES - Abstract
The autoimmune disease immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is caused by mutations in the forkhead box protein P3 (FOXP3) gene. In the mouse model of FOXP3 deficiency, the lack of CD4+ CD25+ Tregs is responsible for lethal autoimmunity, indicating that FOXP3 is required for the differentiation of this Treg subset. We show that the number and phenotype of CD4+ CD25+ T cells from IPEX patients are comparable to those of normal donors. CD4+ CD25high T cells from IPEX patients who express FOXP3 protein suppressed the in vitro proliferation of effector T cells from normal donors, when activated by "weak" TCR stimuli. In contrast, the suppressive function of CD4+ CD25high T cells from IPEX patients who do not express FOXP3 protein was profoundly impaired. Importantly, CD4+ CD25high T cells from either FOXP3+ or FOXP3- IPEX patients showed altered suppression toward autologous effector T cells. Interestingly, IL-2 and IFN-gamma production by PBMCs from IPEX patients was significantly decreased. These findings indicate that FOXP3 mutations in IPEX patients result in heterogeneous biological abnormalities, leading not necessarily to a lack of differentiation of CD4+ CD25high Tregs but rather to a dysfunction in these cells and in effector T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
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