Regulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration

Li, Jiatao; Tan, Jean; Martino, Mikaël M.; Lui, Kathy O.

doi:10.3389/fimmu.2018.00585

Cited by 235 publications

(234 citation statements)

References 113 publications

(150 reference statements)

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“…Much still remains to be determined about how different macrophage populations interact with other cell types in tendon to modulate tissue repair. The adaptive immune system is known to play an important role in tissue pathology in disease states, but its role in healing of various musculoskeletal injuries is an emerging area of study (17), and even less is known about lymphocytes in tendon healing. There is also cross-talk between the innate and adaptive immune systems during tissue repair (12).…”

Section: Discussionmentioning

confidence: 99%

Adaptive and Innate Immune Cell Responses in Tendons and Lymph Nodes After Tendon Injury and Repair

Noah

Martinez

et al. 2019

Preprint

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Tendon injuries are a common clinical condition with limited treatment options. The cellular components of the innate system, such as neutrophils and macrophages, have been well studied in tendon injuries. However the adaptive immune system, comprised of specialized lymphocytes, plays an important role in orchestrating the healing of numerous tissues but less is known about these cells in tendon healing. To gain a greater understanding of the biological processes that regulate tendon healing, we sought to determine how the cellular components of the adaptive and innate immune system respond to a tendon injury using two-month old male mice. We determined that the lymphatic vasculature is present in the epitenon and superficial regions of Achilles tendons. We then created an acute Achilles tenotomy followed by repair, and collected tendons and draining lymph nodes one, two, and four weeks after injury. Using flow cytometry and histology, after tendon injury we observed a robust adaptive immune cell response that followed an initial innate immune cell response. There was an accumulation of monocytes, neutrophils, and macrophages one week after injury that declined thereafter. Dendritic cells and CD4 + T cells peaked two weeks after injury, while B cells and CD8 + T cells progressively increased over time. In parallel, immune cells of the draining popliteal lymph node demonstrated a similarly coordinated response to the injury. These results suggest that there is an adaptive immune response to tendon injury and adaptive immune cells may play a role in regulating tendon healing.

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Section: Discussionmentioning

confidence: 99%

Adaptive and Innate Immune Cell Responses in Tendons and Lymph Nodes After Tendon Injury and Repair

Noah

Martinez

et al. 2019

Preprint

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“…CD4 + T cells are divided into two categories of CD4 + CD25 À effector T cells and CD4 + CD25 + Foxp3 + regulatory T cells (Tregs). Tregs are regarded as anti-inflammatory cells that play a vital role in maintaining immune homeostasis (Lee & Lee 2018) and can facilitate regeneration of various tissues by creating a beneficial immune microenvironment via immune cells modulation or by directly activating progenitor cells (Li et al 2018). Tregs are a specialized subpopulation of T cells.…”

Section: Introductionmentioning

confidence: 99%

“…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). Tregs are regarded as anti-inflammatory cells that play a vital role in maintaining immune homeostasis (Lee & Lee 2018) and can facilitate regeneration of various tissues by creating a beneficial immune microenvironment via immune cells modulation or by directly activating progenitor cells (Li et al 2018). Recently, several studies have reported that MSCs upregulated Tregs, which served to regulate the local or systemic inflammation response to promote tissue regeneration (Wu et al 2014, Liu et al 2015.…”

Section: Introductionmentioning

confidence: 99%

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

Liu

et al. 2019

Int Endodontic J

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Aim To evaluate the expression of Foxp3‐positive lymphocytes around newly formed tissue after regenerative endodontic treatment (RET) in vivo and investigate the effects of stem cells from the apical papilla (SCAP) on the conversion of CD4+CD25− T cells to CD4+CD25+Foxp3+ regulatory T cells (Tregs) in vitro. Methodology Three 6‐month‐old beagles with nine doubled‐rooted premolars in each dog were randomly assigned to the RET group and the control group. RET was performed after apical periodontitis had been induced in the experimental immature teeth. Three months later, the expression of Foxp3 was detected in the histological sections by immunofluorescent staining. Human SCAP and CD4+CD25− T cells from mice spleens (1 : 1 and 1 : 5) were co‐cultured in cell–cell contact or in Transwells, respectively, for 24 and 72 h in vitro. The percentage of Tregs was evaluated by flow cytometry. The results were analysed using the Fisher's exact test and analysis of variance. P < 0.05 was regarded as statistically significant. Results Inflammatory cells were present with tissue regeneration in the RET group, and Foxp3‐positive T cells were enriched around the newly formed tissues. SCAP promoted Treg conversion after 72 h in vitro. Cell–cell contact played an important role after the 24 h co‐culture, whilst soluble factors were also involved after 72 h (P < 0.05). Conclusions SCAP promoted the conversion of pro‐inflammatory T cells to Tregs in vitro. Tregs were enriched around the regenerating tissues in the root canals after RET, which may create a suitable immune microenvironment for the differentiation of SCAP. This study provides an underlying mechanism for tissue regeneration during RET.

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“…One of the underlying mechanisms associated with T reg ‐mediated wound healing is assumed to be the suppression of pro‐inflammatory stimuli. Such T reg ‐mediated immune suppression appears to be a critical factor allowing for the progression of the wound‐healing process . T regs utilize a number of different mechanisms to locally mediate their immune‐suppressive function .…”

Section: Immune‐mediated Roles Of Regulatory T‐cells During Wound Heamentioning

confidence: 99%

“…Such T reg -mediated immune suppression appears to be a critical factor allowing for the progression of the wound-healing process. 13 T regs utilize a number of different mechanisms to locally mediate their immune-suppressive function. 14 These mechanisms include the local activation of bio-active transforming growth factor (TGF)b, 15,16 the secretion of the immune-suppressive cytokine IL-10 17 or the conversion of local adenosine monophosphate into adenosine.…”

Section: Immune-mediated Roles Of Regulatory T-cells During Wound Heamentioning

confidence: 99%

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

2019

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Summary The immune system has a well‐established contribution to tissue homeostasis and wound healing. However, in many cases immune responses themselves can cause severe tissue damage. Thus, the question arose to which extent cells of the immune system directly contribute to the process of wound healing and to which extent the resolution of excessive immune responses may indirectly contribute to wound healing. FoxP3‐expressing CD4 T‐cells, so‐called regulatory T‐cells (Tregs), have an important contribution in the regulation of immune responses; and, in recent years, it has been suggested that Tregs next to an immune‐regulatory, ‘damage‐limiting’ function may also have an immune‐independent ‘damage‐resolving’ direct role in wound healing. In particular, the release of the epidermal growth factor‐like growth factor Amphiregulin by tissue‐resident Tregs during wound repair suggested such a function. Our recent findings have now revealed that Amphiregulin induces the local release of bio‐active transforming growth factor (TGF)β, a cytokine involved both in immune regulation as well as in the process of wound repair. In light of these findings, we discuss whether, by locally activating TGFβ, Treg‐derived Amphiregulin may contribute to both wound repair and immune suppression. Furthermore, we propose that Treg‐derived Amphiregulin in an autocrine way may enable an IL‐33‐mediated survival and expansion of tissue‐resident Tregs upon injury. Furthermore, Treg‐derived Amphiregulin may contribute to a constitutive, low‐level release of bio‐active TGFβ within tissues, leading to continuous tissue regeneration and to an immune‐suppressive environment, which may keep inflammation‐prone tissues in an homeostatic state.

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Regulatory T-Cells: Potential Regulator of Tissue Repair and Regeneration

Cited by 235 publications

References 113 publications

Adaptive and Innate Immune Cell Responses in Tendons and Lymph Nodes After Tendon Injury and Repair

Adaptive and Innate Immune Cell Responses in Tendons and Lymph Nodes After Tendon Injury and Repair

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

Immune‐ and non‐immune‐mediated roles of regulatory T‐cells during wound healing

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