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Regulatory T cells in many flavors control asthma.

Ray A, Khare A, Krishnamoorthy N, Qi Z, Ray P - Mucosal Immunol (2010)

Bottom Line: In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies.This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen.However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. raya@pitt.edu

ABSTRACT
That regulatory T cells (Tregs) have a crucial role in controlling allergic diseases such as asthma is now undisputed. The cytokines most commonly implicated in Treg-mediated suppression of allergic asthma are transforming growth factor-beta (TGF-beta) and interleukin (IL)-10). In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies. The concept of inducible/adaptive Tregs (iTregs) has considerable significance in preventing asthma if generated early enough in life. This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen. However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature. It is tempting to speculate that there is a window of opportunity in early life in the context of a relatively immature immune system that is permissive for the generation of iTregs specific to a spectrum of allergens that would regulate asthma for lifelong. The focus of this review is the relevance of nTregs and iTregs in controlling asthma from early life into adulthood, the mechanisms underlying Treg function, and the prospects for using our current concepts to harness the full potential of Tregs to limit disease development and progression.

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Mucosal tolerance favors iTreg development in lung-draining lymph nodes that have free reign in tolerance but compete with nTregs during inflammation. LAP associated membrane-bound (mTGF-β) on iTregs acts via infectious tolerance to increase its pool size 85. mTGF-β induces Notch activation and upregulation of the downstream repressor Hes1 in naïve CD4+ T cells 27. Hes1 has been shown to stabilize Foxp3 expression in Tregs 114. The iTregs efficiently suppress effector cell development (shown is Th2) in antigen-tolerized animals 26–28,69. In allergen-sensitized animals, the cytokines IL-4 and IL-6 released during priming events suppress Treg induction 94,99,100,224. However, the same cytokines promote nTreg proliferation while inducing Th2 differentiation88,94,224 (Th17 cells are also induced by allergens). The Th2 cells and nTregs traffic to the tissue in recall response to inhaled allergen where they downmodulate costimulatory molecules on DCs 17,18(not shown). If priming occurs at a distant site (skin, spleen), IL-10-expressing Tregs are favored18,30,36,67 which are recruited to the lung in response to allergen challenge to suppress effector T cell functions.
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Figure 2: Mucosal tolerance favors iTreg development in lung-draining lymph nodes that have free reign in tolerance but compete with nTregs during inflammation. LAP associated membrane-bound (mTGF-β) on iTregs acts via infectious tolerance to increase its pool size 85. mTGF-β induces Notch activation and upregulation of the downstream repressor Hes1 in naïve CD4+ T cells 27. Hes1 has been shown to stabilize Foxp3 expression in Tregs 114. The iTregs efficiently suppress effector cell development (shown is Th2) in antigen-tolerized animals 26–28,69. In allergen-sensitized animals, the cytokines IL-4 and IL-6 released during priming events suppress Treg induction 94,99,100,224. However, the same cytokines promote nTreg proliferation while inducing Th2 differentiation88,94,224 (Th17 cells are also induced by allergens). The Th2 cells and nTregs traffic to the tissue in recall response to inhaled allergen where they downmodulate costimulatory molecules on DCs 17,18(not shown). If priming occurs at a distant site (skin, spleen), IL-10-expressing Tregs are favored18,30,36,67 which are recruited to the lung in response to allergen challenge to suppress effector T cell functions.

Mentions: As discussed above, the two molecules that have received the most attention with respect to Treg-mediated suppression of allergic airway inflammation are TGF-β and IL-10. Our investigations showed that membrane-bound TGF-β expressed by Tregs in mice tolerized by inhaled antigen69 activates Notch inducing expression of its downstream target gene Hes1 (hairy and enhancer of split 1) in naïve CD4+ T cells 27. Hes1 is a potent repressor of gene expression 110,111. Simultaneous engagement of TCR, CD28 and Notch was shown to inhibit T cell activation, which was associated with upregulation of Hes1 expression 112. Given that membrane-bound TGF-β, originally identified on activated Tregs 113, has now been implicated in infectious tolerance 85, Hes1 may have an important role in the induction and/or stabilization of Foxp3 expression in the CD4+ T cell destined to become an iTreg. Indeed, Notch activation in Tregs was recently shown to promote Foxp3 expression and stabilize Tregs in vivo114. Figure 2 merges all of these concepts in the context of mucosal tolerance. iTreg development is at a disadvantage during allergen-induced T helper cell differentiation which promotes nTreg proliferation (Figure 2).


Regulatory T cells in many flavors control asthma.

Ray A, Khare A, Krishnamoorthy N, Qi Z, Ray P - Mucosal Immunol (2010)

Mucosal tolerance favors iTreg development in lung-draining lymph nodes that have free reign in tolerance but compete with nTregs during inflammation. LAP associated membrane-bound (mTGF-β) on iTregs acts via infectious tolerance to increase its pool size 85. mTGF-β induces Notch activation and upregulation of the downstream repressor Hes1 in naïve CD4+ T cells 27. Hes1 has been shown to stabilize Foxp3 expression in Tregs 114. The iTregs efficiently suppress effector cell development (shown is Th2) in antigen-tolerized animals 26–28,69. In allergen-sensitized animals, the cytokines IL-4 and IL-6 released during priming events suppress Treg induction 94,99,100,224. However, the same cytokines promote nTreg proliferation while inducing Th2 differentiation88,94,224 (Th17 cells are also induced by allergens). The Th2 cells and nTregs traffic to the tissue in recall response to inhaled allergen where they downmodulate costimulatory molecules on DCs 17,18(not shown). If priming occurs at a distant site (skin, spleen), IL-10-expressing Tregs are favored18,30,36,67 which are recruited to the lung in response to allergen challenge to suppress effector T cell functions.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3039023&req=5

Figure 2: Mucosal tolerance favors iTreg development in lung-draining lymph nodes that have free reign in tolerance but compete with nTregs during inflammation. LAP associated membrane-bound (mTGF-β) on iTregs acts via infectious tolerance to increase its pool size 85. mTGF-β induces Notch activation and upregulation of the downstream repressor Hes1 in naïve CD4+ T cells 27. Hes1 has been shown to stabilize Foxp3 expression in Tregs 114. The iTregs efficiently suppress effector cell development (shown is Th2) in antigen-tolerized animals 26–28,69. In allergen-sensitized animals, the cytokines IL-4 and IL-6 released during priming events suppress Treg induction 94,99,100,224. However, the same cytokines promote nTreg proliferation while inducing Th2 differentiation88,94,224 (Th17 cells are also induced by allergens). The Th2 cells and nTregs traffic to the tissue in recall response to inhaled allergen where they downmodulate costimulatory molecules on DCs 17,18(not shown). If priming occurs at a distant site (skin, spleen), IL-10-expressing Tregs are favored18,30,36,67 which are recruited to the lung in response to allergen challenge to suppress effector T cell functions.
Mentions: As discussed above, the two molecules that have received the most attention with respect to Treg-mediated suppression of allergic airway inflammation are TGF-β and IL-10. Our investigations showed that membrane-bound TGF-β expressed by Tregs in mice tolerized by inhaled antigen69 activates Notch inducing expression of its downstream target gene Hes1 (hairy and enhancer of split 1) in naïve CD4+ T cells 27. Hes1 is a potent repressor of gene expression 110,111. Simultaneous engagement of TCR, CD28 and Notch was shown to inhibit T cell activation, which was associated with upregulation of Hes1 expression 112. Given that membrane-bound TGF-β, originally identified on activated Tregs 113, has now been implicated in infectious tolerance 85, Hes1 may have an important role in the induction and/or stabilization of Foxp3 expression in the CD4+ T cell destined to become an iTreg. Indeed, Notch activation in Tregs was recently shown to promote Foxp3 expression and stabilize Tregs in vivo114. Figure 2 merges all of these concepts in the context of mucosal tolerance. iTreg development is at a disadvantage during allergen-induced T helper cell differentiation which promotes nTreg proliferation (Figure 2).

Bottom Line: In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies.This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen.However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. raya@pitt.edu

ABSTRACT
That regulatory T cells (Tregs) have a crucial role in controlling allergic diseases such as asthma is now undisputed. The cytokines most commonly implicated in Treg-mediated suppression of allergic asthma are transforming growth factor-beta (TGF-beta) and interleukin (IL)-10). In addition to naturally occurring Tregs, adaptive Tregs, induced in response to foreign antigens, have been shown in recent studies. The concept of inducible/adaptive Tregs (iTregs) has considerable significance in preventing asthma if generated early enough in life. This is because cytokines such as IL-4 and IL-6 inhibit Foxp3 induction in naive CD4+ T cells and therefore de novo generation of Tregs can be expected to be less efficient when it is concomitant with effector cell development in response to an allergen. However, if iTregs can be induced, the process of infectious tolerance would facilitate expansion of the iTreg pool as suggested in the recent literature. It is tempting to speculate that there is a window of opportunity in early life in the context of a relatively immature immune system that is permissive for the generation of iTregs specific to a spectrum of allergens that would regulate asthma for lifelong. The focus of this review is the relevance of nTregs and iTregs in controlling asthma from early life into adulthood, the mechanisms underlying Treg function, and the prospects for using our current concepts to harness the full potential of Tregs to limit disease development and progression.

Show MeSH
Related in: MedlinePlus