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

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.

Rejuvenating Strategies for Stem Cell-Based Therapies in Aging

“…T regulatory cells (Tregs), have also received special attention recently due to their ability to dampen inflammatory responses and promote tissue repair in the skeletal muscle, heart, skin, kidney, and brain (Burzyn et al, 2013; Gandolfo et al, 2009; Nosbaum et al, 2016; Raposo et al, 2014; Villalta et al, 2014; Wan et al, 2015; Weirather et al, 2014). Tregs promote regeneration through several mechanisms, including the promotion of anti-inflammatory phenotypes of macrophages, reduction of effector T cells and associated pro-inflammatory signals, and activation of stem/progenitor cells (Lei et al, 2015). At least in the skeletal muscle, this mechanism of immune regulation is also affected by aging: Recruitment of regulatory T cells (Tregs) into skeletal muscle injury sites is impaired in old animals, contributing to age-related loss of regenerative capacity (Kuswanto et al, 2016).…”

Potential immunomodulatory effects of stem cells from the apical papilla on Treg conversion in tissue regeneration for regenerative endodontic treatment

“…Tregs are a specialized subpopulation of T cells. The increased ratio of Tregs and enhanced immune suppression function helps to create an immune microenvironment contributing to tissue regeneration (Lei et al 2015). Tregs are produced in the thymus or converted from naive T cells in the peripheral environment, which is called Treg conversion (Chen et al 2003).…”

‘Repair’ Treg Cells in Tissue Injury

“…First, Tregs regulate tissue repair in an immune-mediated manner. In the context of tissue injury, Tregs restrict the infiltration of inflammatory cells through secretion of immunosuppressive cytokines, which has been well reviewed elsewhere [9]. For example, Tregs directly induce anti-inflammatory macrophages, which contribute to tissue repair during the initiation, maintenance and resolution phases [12, 44-46].…”

“…Recent studies using transgenic mice specifically ablated Tregs have highlighted their nontraditional function in modulating nonimmunological processes through acting on nonimmune targets [7, 8]. The nontraditional role of Tregs in injured tissues has been accepted as a facet of Tregs, which has been shown to be of import in the pro-repair and pro-regenerative process [9]. Of note, although functionally important associations between Tregs and tissue repair after injury have been studied for decades, the cellular mechanisms underlying this process have only recently been revealed by studies examining tissue-resident Tregs [10].…”