357 results on '"Levings, Megan K."'
Search Results
352. Molecular regulation of cellular immunity by FOXP3.
- Author
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McMurchy AN, Di Nunzio S, Roncarolo MG, Bacchetta R, and Levings MK
- Subjects
- Humans, Forkhead Transcription Factors physiology, Gene Expression Regulation physiology, Immunity, Cellular
- Abstract
The immune system is responsible for not only eliminating threats to the body, but also for protecting the body from its own immune responses that would cause harm if left unchecked. Forkhead box protein 3 (FOXP3) is a forkhead family member with an important role in the development and function of a type of CD4+ T cell called T regulatory cells that is fundamental for maintaining immune tolerance to self. This chapter reviews the structure of FOXP3 and how its role in the immune system was discovered. Studies of patients with mutations in FOXP3 who suffer from a syndrome known as IPEX (immune dysregulation, polyendocrinopathy, enteropathy, x-linked) are also discussed. Investigation into how expression of FOXP3 is regulated and how it interacts with other proteins have recently provided considerable insight into mechanisms by which the lack of this protein could cause disease. We also discuss how FOXP3 is involved in the reciprocal development ofT regulatory cells and proinflammatory T-cells that produce IL-17. A better understanding of how FOXP3 is regulated and the molecular basis for its function will ultimately contribute to the development ofT regulatory cell-based cellular therapies that could be used to restore dysregulated immune responses.
- Published
- 2009
353. CD4+ T-regulatory cells: toward therapy for human diseases.
- Author
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Allan SE, Broady R, Gregori S, Himmel ME, Locke N, Roncarolo MG, Bacchetta R, and Levings MK
- Subjects
- Animals, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Graft vs Host Disease prevention & control, Humans, Immune Tolerance, Immunologic Factors therapeutic use, Lymphocyte Activation, Mice, Autoimmune Diseases immunology, Autoimmune Diseases therapy, CD4-Positive T-Lymphocytes immunology, Forkhead Transcription Factors immunology, Immunotherapy, Adoptive, Neoplasms immunology, Neoplasms therapy, T-Lymphocytes, Regulatory immunology
- Abstract
Summary: 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.
- Published
- 2008
- Full Text
- View/download PDF
354. STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25- effector T cells.
- Author
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Passerini L, Allan SE, Battaglia M, Di Nunzio S, Alstad AN, Levings MK, Roncarolo MG, and Bacchetta R
- Subjects
- CD4-Positive T-Lymphocytes drug effects, Cell Line, Cells, Cultured, Enzyme Inhibitors pharmacology, Humans, Immunosuppressive Agents pharmacology, Interleukin-2 pharmacology, Interleukin-2 Receptor alpha Subunit immunology, Signal Transduction, Sirolimus pharmacology, T-Lymphocytes, Regulatory drug effects, CD4-Positive T-Lymphocytes immunology, Forkhead Transcription Factors immunology, Gene Expression Regulation drug effects, STAT5 Transcription Factor immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Forkhead box P3 (FOXP3) is considered a specific marker for CD4(+)CD25(+) regulatory T (Treg) cells, but increasing evidence suggests that human CD4(+)CD25(-) effector T (Teff) cells can transiently express FOXP3 upon activation. We demonstrate that the signal transducer and activator of transcription 5 (STAT5)-signaling cytokines, IL-2, IL-15 and to a lesser extent IL-7, induce FOXP3 up-regulation in vitro in activated human Teff cells. In contrast, cytokines which do not activate STAT5, such as IL-4 or transforming growth factor-beta alone, do not directly induce FOXP3 expression in activated Teff cells. Moreover, expression of a constitutively active form of STAT5a is sufficient to induce FOXP3 expression in Teff cells. Expression of FOXP3 in activated Teff cells requires both TCR-mediated activation and endogenous IL-2, but is not dependent on cell division and does not induce suppressive function. The presence of STAT5-activating cytokines is also required to maintain high FOXP3 expression and suppressive activity of Treg cells in vitro. These data indicate that activation of STAT5 sustains FOXP3 expression in both Treg and Teff cells and contribute to our understanding of how cytokines affect the expression of FOXP3.
- Published
- 2008
- Full Text
- View/download PDF
355. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production.
- Author
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Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, Roncarolo MG, and Levings MK
- Subjects
- Antibodies pharmacology, Antigens, CD metabolism, Antigens, Differentiation metabolism, Antigens, Differentiation, T-Lymphocyte metabolism, CD28 Antigens immunology, CD3 Complex immunology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CTLA-4 Antigen, Cell Line, Clonal Anergy, Coculture Techniques, Cysteine analogs & derivatives, Cysteine pharmacology, Flagellin pharmacology, Glucocorticoid-Induced TNFR-Related Protein, Humans, Interferon-gamma metabolism, Interleukin-2 metabolism, Interleukin-2 pharmacology, Interleukin-2 Receptor alpha Subunit metabolism, Interleukin-7 Receptor alpha Subunit metabolism, Lectins, C-Type, Lipoproteins pharmacology, Lymphocyte Activation immunology, Receptors, Nerve Growth Factor metabolism, Receptors, Tumor Necrosis Factor metabolism, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets immunology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Toll-Like Receptors immunology, Cell Proliferation, Cytokines metabolism, Forkhead Transcription Factors metabolism, T-Lymphocyte Subsets metabolism
- Abstract
Forkhead box P3 (FOXP3) is currently thought to be the most specific marker for naturally occurring CD4(+)CD25(+) T regulatory cells (nTregs). In mice, expression of FoxP3 is strictly correlated with regulatory activity, whereas increasing evidence suggests that in humans, activated T effector cells (Teffs) may also express FOXP3. In order to better define the role of FOXP3 in human Teff cells, we investigated the intensity and kinetics of expression in ex vivo Teff cells, suppressed Teff cells and Teff cell lines. We found that all dividing Teff cells expressed FOXP3, but only transiently, and at levels that were significantly lower than those in suppressive nTregs. This temporary expression in Teff cells was insufficient to suppress expression of reported targets of FOXP3 repressor activity, including CD127, IL-2 and IFN-gamma, and was not correlated with induction of a nTreg phenotype. Thus expression of FOXP3 is a normal consequence of CD4(+) T cell activation and, in humans, it can no longer be used as an exclusive marker of nTregs. These data indicate that our current understanding of how FOXP3 contributes to immune tolerance in humans needs to be re-evaluated.
- Published
- 2007
- Full Text
- View/download PDF
356. Isolation, expansion, and characterization of human natural and adaptive regulatory T cells.
- Author
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Gregori S, Bacchetta R, Passerini L, Levings MK, and Roncarolo MG
- Subjects
- Cell Culture Techniques methods, Flow Cytometry methods, Humans, Immunity, Innate immunology, Cell Proliferation, Cell Separation methods, T-Lymphocyte Subsets immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Regulatory T cells play a central role in controlling homeostasis, and in inducing and maintaining tolerance to both foreign and self-antigens. Several types of T cells with regulatory activity have been described both in mice and humans, and those within the CD4+ subset have been extensively studied. Among them, the best characterized are the naturally occurring CD4+CD25+ regulatory T (Treg) cells, and the adaptive type 1 regulatory T (Tr1) cells. Natural Treg cells can arise directly from the thymus, are characterized by the constitutive expression of the transcription factor Foxp3, and suppress T cell responses in a cell-cell contact mediated mechanism. On the contrary, adaptive Tr1 cells arise in the periphery upon encountering antigen in a tolerogenic environment, produce high levels of interleukin (IL)-10 and mediate suppression via IL-10. During the last decade, much effort has been placed on developing protocols to generate regulatory T-cell lines and clones, to further define the similarities and differences between various regulatory T-cell subsets. In this chapter, we will outline protocols to expand naturally occurring Treg cells, to differentiate homogeneous population of Tr1 cells in vitro, and to generate natural Treg and Tr1 cell clones and cell lines.
- Published
- 2007
- Full Text
- View/download PDF
357. Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells.
- Author
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Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC, and Roncarolo MG
- Subjects
- Abatacept, Antigens, CD, Antigens, Differentiation immunology, CTLA-4 Antigen, Clonal Anergy immunology, Clone Cells, Coculture Techniques, Enzyme-Linked Immunosorbent Assay, Humans, Interleukin-10 immunology, T-Lymphocytes, Regulatory immunology, CD4 Antigens immunology, Immunoconjugates, Interleukin-10 biosynthesis, Receptors, Interleukin-2 immunology, T-Lymphocytes, Regulatory metabolism, Transforming Growth Factor beta biosynthesis
- Abstract
T regulatory (Tr) cells are essential for the induction of peripheral tolerance. Several types of Tr cells exist, including CD4(+) T cells which express CD25 constitutively and suppress immune responses via direct cell-to-cell interactions, and type 1 T regulatory (Tr1) cells, which function via secretion of interleukin (IL)-10 and transforming growth factor (TGF)-beta. The relationship between CD25(+)CD4(+) T cells and Tr1 cells remains unclear. Here, we demonstrate at the clonal level that Tr1 and CD25(+)CD4(+) T cells are two distinct subsets of regulatory cells with different cytokine production profiles. Furthermore, CD25(-)CD4(+) T cells can be rendered anergic by IL-10 and differentiated into Tr1 cells in the absence of CD25(+)CD4(+) T cells. Cloned human CD25(+)CD4(+) T cell populations are heterogeneous and only a subset of clones continues to express high levels of CD25 and is suppressive. The intensity of CD25, cytotoxic T lymphocyte antigen (CTLA)-4, and glucocorticoid-induced tumor necrosis factor (TNF) receptor expression correlates with the suppressive capacity of the T cell clones. None of the CD25(+)CD4(+) T cell clones with suppressive function produce IL-10, but all produce TGF-beta. Suppression mediated by CD25(+)CD4(+) T cell clones is partially dependent on TGF-beta, but not on constitutive high expression of CD25. Together these data indicate that naturally occurring human CD25(+)CD4(+) T cells are distinct from IL-10-producing Tr1 cells.
- Published
- 2002
- Full Text
- View/download PDF
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