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Regulatory T cell-mediated anti-inflammatory effects promote successful tissue repair in both indirect and direct manners.

Lei H, Schmidt-Bleek K, Dienelt A, Reinke P, Volk HD - Front Pharmacol (2015)

Bottom Line: We describe tissue-resident Treg and their specific phenotypes in skin, visceral adipose tissue, and skeletal muscle.We hypothesize a cross-talk between Treg and bone-forming cells through the CD39-CD73-(adenosine)-adenosine receptor pathway, which might also potentiate the differentiation of MSCs, thus facilitating bone regeneration.This hypothesis may provide a road map for further investigations on the cross-talk between the immune and the skeletal system, and also enable the development of better strategies to promote bone repair and regeneration.

View Article: PubMed Central - PubMed

Affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin , Berlin, Germany ; Institute for Medical Immunology, Charité University Medicine Berlin , Berlin, Germany.

ABSTRACT
Regulatory T cells (Tregs) offer new immunotherapeutic options to control undesired immune reactions, such as those in transplant rejection and autoimmunity. In addition, tissue repair and regeneration depend on a multitude of tightly regulated immune and non-immune cells and signaling molecules. There is mounting evidence that adequate innate responses, and even more importantly balanced adaptive immune responses, are key players in the tissue repair and regeneration processes, even in absence of any immune-related disease or infection. Thus, the anti-inflammatory and anti-apoptotic capacities of Treg can affect not only the effector immune response, creating the appropriate immune environment for successful tissue repair and regeneration, but growing evidence shows that they also have direct effects on tissue cell functions. Here we summarize the present views on how Treg might support tissue regeneration by direct control of undesired immune reactivity and also by direct interaction with non-immune tissue cells. We describe tissue-resident Treg and their specific phenotypes in skin, visceral adipose tissue, and skeletal muscle. In addition, we touch on the topic of osteoimmunology, discussing the direct interactions of Treg with bone-forming cells, such as osteoblasts and their mesenchymal stromal cell (MSC) progenitors-a field which is under-investigated. We hypothesize a cross-talk between Treg and bone-forming cells through the CD39-CD73-(adenosine)-adenosine receptor pathway, which might also potentiate the differentiation of MSCs, thus facilitating bone regeneration. This hypothesis may provide a road map for further investigations on the cross-talk between the immune and the skeletal system, and also enable the development of better strategies to promote bone repair and regeneration.

No MeSH data available.


Related in: MedlinePlus

Hypothesized direct cross-talk between Treg and osteoblasts (MSCs). (i) CD39 expressing Treg may co-operate with CD73 expressing osteoblasts (MSCs) to hydrolyze ATP to form adenosine, which can further bind to its receptor on osteoblasts (ADOR) to trigger the inhibitory pathways; (ii) Treg may up-regulate IDO and HO-1 expression on osteoblasts; (iii) Treg play a role in the balance of RANKL/OPG, thus facilitating osteoblast differentiation.
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Figure 3: Hypothesized direct cross-talk between Treg and osteoblasts (MSCs). (i) CD39 expressing Treg may co-operate with CD73 expressing osteoblasts (MSCs) to hydrolyze ATP to form adenosine, which can further bind to its receptor on osteoblasts (ADOR) to trigger the inhibitory pathways; (ii) Treg may up-regulate IDO and HO-1 expression on osteoblasts; (iii) Treg play a role in the balance of RANKL/OPG, thus facilitating osteoblast differentiation.

Mentions: It is known that both Treg and MSCs use the CD39–CD73-mediated adenosine-producing pathway to control inflammation. However, the dominant tTreg population mainly expresses CD39 (ENTPD1) rather than CD73 (NT5E), while bone marrow-derived MSCs mainly express CD73 rather than CD39 in human. We and others have shown that human Treg produce adenosine upon contact with CD73+ cells (Saldanha-Araujo et al., 2011; Schuler et al., 2014; Zhang et al., 2015). Therefore, it is possible that Treg cooperate with MSCs to convert ATP into adenosine. The resulting adenosine can signal via 4 receptor subtypes: adenosine receptor A1 (ADORA1), ADORA2A, ADORA2B, and ADORA3. Undifferentiated bone marrow-derived MSCs mainly express ADORA2B. Various receptors are important for particular differentiation outcomes. ADORA2B is the essential receptor for MSCs differentiation into OBs, enabling bone formation, while ADORA1 and ADORA2A are more related with MSC differentiation toward adipocytes (Gharibi et al., 2011; Trincavelli et al., 2014). Based on these facts, we hypothesize that Treg could act directly on OBs through coordination of the CD39–CD73-(adenosine)-ADOR pathway (Figure 3). This coordination regarding purinergic signaling may also exist between Treg and the tissue progenitor cells, which could potentiate the differentiation of MSCs and thus facilitate tissue regeneration. IDO and HO-1 induction by Treg on OBs may also be a result of direct cross-talk between Treg and OBs (Oliveira et al., 2006).


Regulatory T cell-mediated anti-inflammatory effects promote successful tissue repair in both indirect and direct manners.

Lei H, Schmidt-Bleek K, Dienelt A, Reinke P, Volk HD - Front Pharmacol (2015)

Hypothesized direct cross-talk between Treg and osteoblasts (MSCs). (i) CD39 expressing Treg may co-operate with CD73 expressing osteoblasts (MSCs) to hydrolyze ATP to form adenosine, which can further bind to its receptor on osteoblasts (ADOR) to trigger the inhibitory pathways; (ii) Treg may up-regulate IDO and HO-1 expression on osteoblasts; (iii) Treg play a role in the balance of RANKL/OPG, thus facilitating osteoblast differentiation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557110&req=5

Figure 3: Hypothesized direct cross-talk between Treg and osteoblasts (MSCs). (i) CD39 expressing Treg may co-operate with CD73 expressing osteoblasts (MSCs) to hydrolyze ATP to form adenosine, which can further bind to its receptor on osteoblasts (ADOR) to trigger the inhibitory pathways; (ii) Treg may up-regulate IDO and HO-1 expression on osteoblasts; (iii) Treg play a role in the balance of RANKL/OPG, thus facilitating osteoblast differentiation.
Mentions: It is known that both Treg and MSCs use the CD39–CD73-mediated adenosine-producing pathway to control inflammation. However, the dominant tTreg population mainly expresses CD39 (ENTPD1) rather than CD73 (NT5E), while bone marrow-derived MSCs mainly express CD73 rather than CD39 in human. We and others have shown that human Treg produce adenosine upon contact with CD73+ cells (Saldanha-Araujo et al., 2011; Schuler et al., 2014; Zhang et al., 2015). Therefore, it is possible that Treg cooperate with MSCs to convert ATP into adenosine. The resulting adenosine can signal via 4 receptor subtypes: adenosine receptor A1 (ADORA1), ADORA2A, ADORA2B, and ADORA3. Undifferentiated bone marrow-derived MSCs mainly express ADORA2B. Various receptors are important for particular differentiation outcomes. ADORA2B is the essential receptor for MSCs differentiation into OBs, enabling bone formation, while ADORA1 and ADORA2A are more related with MSC differentiation toward adipocytes (Gharibi et al., 2011; Trincavelli et al., 2014). Based on these facts, we hypothesize that Treg could act directly on OBs through coordination of the CD39–CD73-(adenosine)-ADOR pathway (Figure 3). This coordination regarding purinergic signaling may also exist between Treg and the tissue progenitor cells, which could potentiate the differentiation of MSCs and thus facilitate tissue regeneration. IDO and HO-1 induction by Treg on OBs may also be a result of direct cross-talk between Treg and OBs (Oliveira et al., 2006).

Bottom Line: We describe tissue-resident Treg and their specific phenotypes in skin, visceral adipose tissue, and skeletal muscle.We hypothesize a cross-talk between Treg and bone-forming cells through the CD39-CD73-(adenosine)-adenosine receptor pathway, which might also potentiate the differentiation of MSCs, thus facilitating bone regeneration.This hypothesis may provide a road map for further investigations on the cross-talk between the immune and the skeletal system, and also enable the development of better strategies to promote bone repair and regeneration.

View Article: PubMed Central - PubMed

Affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité University Medicine Berlin , Berlin, Germany ; Institute for Medical Immunology, Charité University Medicine Berlin , Berlin, Germany.

ABSTRACT
Regulatory T cells (Tregs) offer new immunotherapeutic options to control undesired immune reactions, such as those in transplant rejection and autoimmunity. In addition, tissue repair and regeneration depend on a multitude of tightly regulated immune and non-immune cells and signaling molecules. There is mounting evidence that adequate innate responses, and even more importantly balanced adaptive immune responses, are key players in the tissue repair and regeneration processes, even in absence of any immune-related disease or infection. Thus, the anti-inflammatory and anti-apoptotic capacities of Treg can affect not only the effector immune response, creating the appropriate immune environment for successful tissue repair and regeneration, but growing evidence shows that they also have direct effects on tissue cell functions. Here we summarize the present views on how Treg might support tissue regeneration by direct control of undesired immune reactivity and also by direct interaction with non-immune tissue cells. We describe tissue-resident Treg and their specific phenotypes in skin, visceral adipose tissue, and skeletal muscle. In addition, we touch on the topic of osteoimmunology, discussing the direct interactions of Treg with bone-forming cells, such as osteoblasts and their mesenchymal stromal cell (MSC) progenitors-a field which is under-investigated. We hypothesize a cross-talk between Treg and bone-forming cells through the CD39-CD73-(adenosine)-adenosine receptor pathway, which might also potentiate the differentiation of MSCs, thus facilitating bone regeneration. This hypothesis may provide a road map for further investigations on the cross-talk between the immune and the skeletal system, and also enable the development of better strategies to promote bone repair and regeneration.

No MeSH data available.


Related in: MedlinePlus