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. 2015 Sep 2:6:184.
doi: 10.3389/fphar.2015.00184. eCollection 2015.

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

Hong Lei  1 , Katharina Schmidt-Bleek  2 , Anke Dienelt  2 , Petra Reinke  3 , Hans-Dieter Volk  1
Affiliations

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

Hong Lei et al. Front Pharmacol. .

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.

Keywords: inflammation; osteoblasts; purinergic signaling; regulatory T cells; tissue regeneration.

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Figures

FIGURE 1
FIGURE 1
Molecular mechanisms used by Treg for the suppression of immune cells.
FIGURE 2
FIGURE 2
A proportion of Treg express an effector-memory phenotype in healthy donors. (A) Proportions of Treg subsets in total Treg in healthy donors (mean ± SD, n = 36, age 19–87 years). (B) A significant proportion of expanded naïve (TregN) and central-memory Treg (TregCM) converted into EM (CD45RA–CD62L–) phenotype upon 3 weeks of expansion with poly-clonal stimulation in the presence of rapamycin and interleukin 2. The mean frequency of cells expressing an EM phenotype is indicated for each cell type before and after expansion. (n = 5), paired t-test, taken from Lei et al. (2015) **p < 0.01.
FIGURE 3
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.
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