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Role of Regulatory T Cells in Tolerance: Implication in Human Diseases

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Air date: Wednesday, March 24, 2010, 3:00:00 PM
Time displayed is Eastern Time, Washington DC Local
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Category: Wednesday Afternoon Lectures
Runtime: 00:55:11
Description: Cells with regulatory function exist within all major T and NK cell subsets. Most attention has been focused on regulatory T (Tr) cells with a CD4+ phenotype: the naturally occurring Tr (nTreg) cells and the adaptive type 1 Tr (Tr1) cells. These two subsets of Tr cells, which are developmentally and functionally distinct, cooperate in suppressing activation of the immune system and thereby in maintaining immunological homeostasis and inducing tolerance to self and foreign antigens.

nTreg cells arise from the thymus and their suppressor function is strictly dependent on high expression of the transcription factor FOXP3, whereas Tr1 cells are induced in the periphery upon chronic stimulation with antigen in the presence of IL-10, secrete high levels of IL-10 in the absence of IL-4, and suppress antigen presenting cells and effector T cells through a cytokine-dependent mechanism. In humans, the presence of Tr1 cells is associated with tolerance, whereas defects in nTreg or Tr1 cells lead to autoimmune mediated diseases or to chronic inflammation, respectively.

We and others have dedicated much effort to establish methods to isolate and expand nTreg cells or to induce antigen-specific Tr1 cells ex vivo to be used as cell therapy to promote or rebuilt tolerance. We established a protocol to selectively expand CD4+CD25+FOXP3+ T cells with suppressive activity using rapamycin. Alternatively, we showed that exogenous IL-10 or IL-10-derived from tolerogenic dendritic cells promote the in vitro induction of Tr1 cells. Moreover, we are exploring a novel approach to generate a homogeneous population of antigen-specific Tr cells using lentiviral vector mediated gene transfer.

Alternatively, to the use of ex vivo expanded/differentiated Tr cells, these cells can be induced directly in vivo. We demonstrated that a combination therapy with depleting agents (i.e. anti CD45 mAb) and rapamycin/IL-10 treatment efficiently promoted tolerance via the induction of both nTreg and Tr1 cells. In addition, we recently showed that a small molecular weight compound that specifically activates the aryl hydrocarbon receptor is able to induce tolerance through a direct or DC mediated effects on Tr cells.

These approaches represent the first step towards the definition of new therapeutic protocols aimed to suppress pathology and restore peripheral tolerance in immune-mediated diseases.

Lecture Objectives:
    1. Specify the major characteristics of human nTreg and Tr1 cells.
    2. Define the role for FOXP3 in different subset of human Tr cells.
    3. Outline approaches used to expand/generate human Tr cells in vitro and in vivo.

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NLM Title: Role of regulatory T cells in tolerance : implication in human diseases [electronic resource] / Maria Grazia Roncarolo.
Series: NIH Wednesday afternoon lecture series
Author: Roncarolo, Maria-Grazia.
National Institutes of Health (U.S.)
Publisher:
Other Title(s): NIH Wednesday afternoon lecture series
Abstract: (CIT): Cells with regulatory function exist within all major T and NK cell subsets. Most attention has been focused on regulatory T (Tr) cells with a CD4+ phenotype: the naturally occurring Tr (nTreg) cells and the adaptive type 1 Tr (Tr1) cells. These two subsets of Tr cells, which are developmentally and functionally distinct, cooperate in suppressing activation of the immune system and thereby in maintaining immunological homeostasis and inducing tolerance to self and foreign antigens. nTreg cells arise from the thymus and their suppressor function is strictly dependent on high expression of the transcription factor FOXP3, whereas Tr1 cells are induced in the periphery upon chronic stimulation with antigen in the presence of IL-10, secrete high levels of IL-10 in the absence of IL-4, and suppress antigen presenting cells and effector T cells through a cytokine-dependent mechanism. In humans, the presence of Tr1 cells is associated with tolerance, whereas defects in nTreg or Tr1 cells lead to autoimmune mediated diseases or to chronic inflammation, respectively. We and others have dedicated much effort to establish methods to isolate and expand nTreg cells or to induce antigen-specific Tr1 cells ex vivo to be used as cell therapy to promote or rebuilt tolerance. We established a protocol to selectively expand CD4+CD25+FOXP3+ T cells with suppressive activity using rapamycin. Alternatively, we showed that exogenous IL-10 or IL-10-derived from tolerogenic dendritic cells promote the in vitro induction of Tr1 cells. Moreover, we are exploring a novel approach to generate a homogeneous population of antigen-specific Tr cells using lentiviral vector mediated gene transfer. Alternatively, to the use of ex vivo expanded/differentiated Tr cells, these cells can be induced directly in vivo. We demonstrated that a combination therapy with depleting agents (i.e. anti CD45 mAb) and rapamycin/IL-10 treatment efficiently promoted tolerance via the induction of both nTreg and Tr1 cells. In addition, we recently showed that a small molecular weight compound that specifically activates the aryl hydrocarbon receptor is able to induce tolerance through a direct or DC mediated effects on Tr cells. These approaches represent the first step towards the definition of new therapeutic protocols aimed to suppress pathology and restore peripheral tolerance in immune-mediated diseases.
Subjects: Forkhead Transcription Factors
Immune Tolerance
T-Lymphocytes, Regulatory--immunology
Publication Types: Lectures
Webcasts
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NLM Classification: QW 568
NLM ID: 101528451
CIT Live ID: 8636
Permanent link: http://videocast.nih.gov/launch.asp?15755

 

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