Limits...
Microbiota, regulatory T cell subsets, and allergic disorders

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In contrast, it is well known that exposure of naive T cells to the cytokine IL-4 is a key event for triggering Th2 differentiation which will become self-sustaining as soon as the differentiating Th2 cells start to produce this cytokine themselves... However, a variety of innate or “innate-like” cells that carry the transcriptional capacity to rapidly secrete IL-4 without prior differentiation steps were identified in newly generated reporter mice; these include basophils, eosinophils, mast cells, γδ T cells, and natural killer T (NKT) cells... First, in the lung, the complete absence of microbes leads to a more severe form of ovalbumin-induced allergic airway inflammation... Similarly, the treatment with antibiotics early in life resulted in a profound increase of susceptibility to allergic airway inflammation... Secondly, the specific knockout of several pathways or costimulatory molecules within Foxp3 Tregs in mice has been associated with spontaneously increased IgE levels: the knockout of interferon regulatory factor 4 (IRF4) in Tregs results in enhanced generation of Th2 cells and plasma cells that generate high levels of IgE... Similarly, the knockout of the cytotoxic T lymphocyte antigen 4 (CLTA-4) in Tregs results in fatal autoimmunity characterized among other defects by heightened IgE levels and increased numbers of IL-4 producing Th2 cells... Surprisingly, Tregs can also co-express some of these transcription factors... Others and we recently found that non-self specific Tregs in the gut do not express Helios but surprisingly express the pro-inflammatory transcription factor retinoic acid-related orphan receptor gamma t [ROR(γt)]1... It should be noted that colonization with a clostridia consortium – that has been previously associated to Treg induction – preferentially but not exclusively induces ROR(γt) Tregs... Similarly, we found a biased induction of ROR(γt) Tregs after treatment with the SCFA butyrate but Sefik et al. did not... Indeed, the knockout of IL-6 and its signal transducer STAT3 (both of which critical factors for the differentiation of Th17 cells) results in reduced frequencies of ROR(γt) Tregs... For the effect of IL-23, a cytokine involved in Th17 cell differentiation, the Benoist group and we obtained divergent results: in the absence of IL-23, we observed a reduced frequency of ROR(γt) Tregs whereas the group of Benoist did not... We found that these Foxp3 × ROR(γt) mice showed slightly reduced frequencies of Helios− Foxp3+ iTregs in the small intestinal lamina propria... In parallel to the genetically induced reduction of ROR(γt) Tregs, we found a relative increase of Gata3 Tregs and a slight increase of Gata3 Th2 cells and serum IgE levels... Two observations make it unlikely that Gata3 Tregs are induced upon recognition of foreign antigens/allergens: firstly, Gata3 Tregs do at least to a certain degree express Helios (and may thus be rather of thymic origin and/or recognize self antigens) and secondly, Gata3 Tregs can still be found in germfree mice (Fig. 1).

No MeSH data available.


Related in: MedlinePlus

Suppression of type 2 immune responses through type 3 regulatory T cells. Possible mechanism for the relation between microbiota, ROR(γt)+ Tregs, and prevention of pro-allergic Th2 immune responses. Unwanted Th2 differentiation in response to harmless foreign antigens such as allergens is suppressed through the induction of ROR(γt)+ Tregs under healthy conditions. Th2 differentiation may be favored through an “altered” microbiota at mucosal sites.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC5016534&req=5

Fig2: Suppression of type 2 immune responses through type 3 regulatory T cells. Possible mechanism for the relation between microbiota, ROR(γt)+ Tregs, and prevention of pro-allergic Th2 immune responses. Unwanted Th2 differentiation in response to harmless foreign antigens such as allergens is suppressed through the induction of ROR(γt)+ Tregs under healthy conditions. Th2 differentiation may be favored through an “altered” microbiota at mucosal sites.

Mentions: But how can ROR(γt)+ Treg exert this specific function? In general, it is not really known by which of their multiple regulatory mechanism Tregs exert their regulatory function in a defined immune response. Nevertheless, we found that ROR(γt)+ Tregs may alter the phenotype of intestinal dendritic cells because Foxp3Cre x ROR(γt)FL/FL mice showed lower levels of the costimulatory receptors CD80 and CD86 [60] similar to what has been observed in CTLA-4-deficient Tregs [55]. ROR(γt)+ Tregs do express high levels of CTLA-4 and IRF4 at steady state which is in line with the Th2 bias observed in mice with a selective defect of these molecules in Foxp3+ Tregs [54, 55]. Altogether, these results point towards a fundamental role of ROR(γt)+ Tregs in the control of Th2-dominated immune responses under certain circumstances (Fig. 2). As the differentiation of Th17 cells and ROR(γt)+ Tregs seem to share at least some transcriptional programs, one can ask whether this program is generally used to counteract Th2 immune responses. Indeed, one study recently highlighted a possible Th2 and Th17 counter regulation in the case of allergic asthma [72]. This does not exclude that mixed Th2/Th17 phenotypes of allergic disorders exist because genetic factors may unleash this reciprocal regulation and result in even more severe forms of allergic asthma [73, 74].


Microbiota, regulatory T cell subsets, and allergic disorders
Suppression of type 2 immune responses through type 3 regulatory T cells. Possible mechanism for the relation between microbiota, ROR(γt)+ Tregs, and prevention of pro-allergic Th2 immune responses. Unwanted Th2 differentiation in response to harmless foreign antigens such as allergens is suppressed through the induction of ROR(γt)+ Tregs under healthy conditions. Th2 differentiation may be favored through an “altered” microbiota at mucosal sites.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5016534&req=5

Fig2: Suppression of type 2 immune responses through type 3 regulatory T cells. Possible mechanism for the relation between microbiota, ROR(γt)+ Tregs, and prevention of pro-allergic Th2 immune responses. Unwanted Th2 differentiation in response to harmless foreign antigens such as allergens is suppressed through the induction of ROR(γt)+ Tregs under healthy conditions. Th2 differentiation may be favored through an “altered” microbiota at mucosal sites.
Mentions: But how can ROR(γt)+ Treg exert this specific function? In general, it is not really known by which of their multiple regulatory mechanism Tregs exert their regulatory function in a defined immune response. Nevertheless, we found that ROR(γt)+ Tregs may alter the phenotype of intestinal dendritic cells because Foxp3Cre x ROR(γt)FL/FL mice showed lower levels of the costimulatory receptors CD80 and CD86 [60] similar to what has been observed in CTLA-4-deficient Tregs [55]. ROR(γt)+ Tregs do express high levels of CTLA-4 and IRF4 at steady state which is in line with the Th2 bias observed in mice with a selective defect of these molecules in Foxp3+ Tregs [54, 55]. Altogether, these results point towards a fundamental role of ROR(γt)+ Tregs in the control of Th2-dominated immune responses under certain circumstances (Fig. 2). As the differentiation of Th17 cells and ROR(γt)+ Tregs seem to share at least some transcriptional programs, one can ask whether this program is generally used to counteract Th2 immune responses. Indeed, one study recently highlighted a possible Th2 and Th17 counter regulation in the case of allergic asthma [72]. This does not exclude that mixed Th2/Th17 phenotypes of allergic disorders exist because genetic factors may unleash this reciprocal regulation and result in even more severe forms of allergic asthma [73, 74].

View Article: PubMed Central - PubMed

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

In contrast, it is well known that exposure of naive T cells to the cytokine IL-4 is a key event for triggering Th2 differentiation which will become self-sustaining as soon as the differentiating Th2 cells start to produce this cytokine themselves... However, a variety of innate or “innate-like” cells that carry the transcriptional capacity to rapidly secrete IL-4 without prior differentiation steps were identified in newly generated reporter mice; these include basophils, eosinophils, mast cells, γδ T cells, and natural killer T (NKT) cells... First, in the lung, the complete absence of microbes leads to a more severe form of ovalbumin-induced allergic airway inflammation... Similarly, the treatment with antibiotics early in life resulted in a profound increase of susceptibility to allergic airway inflammation... Secondly, the specific knockout of several pathways or costimulatory molecules within Foxp3 Tregs in mice has been associated with spontaneously increased IgE levels: the knockout of interferon regulatory factor 4 (IRF4) in Tregs results in enhanced generation of Th2 cells and plasma cells that generate high levels of IgE... Similarly, the knockout of the cytotoxic T lymphocyte antigen 4 (CLTA-4) in Tregs results in fatal autoimmunity characterized among other defects by heightened IgE levels and increased numbers of IL-4 producing Th2 cells... Surprisingly, Tregs can also co-express some of these transcription factors... Others and we recently found that non-self specific Tregs in the gut do not express Helios but surprisingly express the pro-inflammatory transcription factor retinoic acid-related orphan receptor gamma t [ROR(γt)]1... It should be noted that colonization with a clostridia consortium – that has been previously associated to Treg induction – preferentially but not exclusively induces ROR(γt) Tregs... Similarly, we found a biased induction of ROR(γt) Tregs after treatment with the SCFA butyrate but Sefik et al. did not... Indeed, the knockout of IL-6 and its signal transducer STAT3 (both of which critical factors for the differentiation of Th17 cells) results in reduced frequencies of ROR(γt) Tregs... For the effect of IL-23, a cytokine involved in Th17 cell differentiation, the Benoist group and we obtained divergent results: in the absence of IL-23, we observed a reduced frequency of ROR(γt) Tregs whereas the group of Benoist did not... We found that these Foxp3 × ROR(γt) mice showed slightly reduced frequencies of Helios− Foxp3+ iTregs in the small intestinal lamina propria... In parallel to the genetically induced reduction of ROR(γt) Tregs, we found a relative increase of Gata3 Tregs and a slight increase of Gata3 Th2 cells and serum IgE levels... Two observations make it unlikely that Gata3 Tregs are induced upon recognition of foreign antigens/allergens: firstly, Gata3 Tregs do at least to a certain degree express Helios (and may thus be rather of thymic origin and/or recognize self antigens) and secondly, Gata3 Tregs can still be found in germfree mice (Fig. 1).

No MeSH data available.


Related in: MedlinePlus