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   Table of Contents    
REVIEW ARTICLE
Year : 2021  |  Volume : 25  |  Issue : 4  |  Page : 278-282  

Evidence revealing the role of T cell regulators (Tregs) in periodontal diseases: A review


1 Department of Periodontics, Priyadarshini Dental College and Hospital, Thiruvallur, India
2 Department of Pedodontics, Thai Moogambigai Dental College and Hospital, Chennai, Tamil Nadu, India
3 Department of Periodontics, Indira Gandhi Dental College and Hospital, Puducherry, India

Date of Submission28-Apr-2020
Date of Decision19-Dec-2020
Date of Acceptance26-Jan-2021
Date of Web Publication01-Jul-2021

Correspondence Address:
Paavai Ilango
Priyadarshini Dental College and Hospital, No. 1. V. G. R Gardens, V. G. R. Nagar, Pandur, Thiruvallur - 631 203, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jisp.jisp_308_20

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   Abstract 


Periodontitis is an inflammatory disease of the periodontium, which is a reflection of the overgrowth of oral commensals. This alteration in the oral microbiota initiates inflammation of the gingiva, which when left untreated, terminates with the resorption of the alveolar bone that may lead to a poor and hopeless prognosis. With upcoming trends in modulating the host's immunity, the role of regulatory T-cells has gained importance. These T-cells defend against inflammation and autoimmunity as they suppress both. However, in both the conditions, the regulatory cells are invariably reduced in number. Novel methods to enhance the function of Tregs have made their way in dentistry, as a promising approach to cure periodontitis. This article discusses various significant tests and trials of Tregs in the recent years.

Keywords: Immunity, immuno-modulation, periodontitis, regulatory T-cells, Treg cell therapy


How to cite this article:
Ilango P, Kumar D, Mahalingam A, Thanigaimalai A, Reddy VK. Evidence revealing the role of T cell regulators (Tregs) in periodontal diseases: A review. J Indian Soc Periodontol 2021;25:278-82

How to cite this URL:
Ilango P, Kumar D, Mahalingam A, Thanigaimalai A, Reddy VK. Evidence revealing the role of T cell regulators (Tregs) in periodontal diseases: A review. J Indian Soc Periodontol [serial online] 2021 [cited 2021 Sep 27];25:278-82. Available from: https://www.jisponline.com/text.asp?2021/25/4/278/319657




   Introduction Top


Periodontium is a complex structure comprising of the gingiva, the alveolar bone, the periodontal ligament, and the cementum. Being amply nourished by blood, it has certain protective features such as keratinized mucosa and gingival crevicular fluid, to defend it from any sort of thermal, chemical, traumatic, or infectious insults. Despite these barriers, they are prone for periodontitis primarily due to poor oral hygiene, influenced by genetic, environmental, and systemic risk factors.

Periodontal microbiology

Periodontitis begins as an inflammation of the gingiva as a response to bacteria. A healthy oral microbiota has predominantly Gram positive bacteria, while in periodontitis, Gram negative bacteria predominate. A healthy periodontium resolves the inflammation by neutralizing the pathogen, whereas a compromised periodontium fails to do the same. According to specific plaque hypothesis, the pathogenicity of the bacteria influences periodontitis, more than the quantity of the bacteria. In accordance with this, there are four keystone perio pathogens namely Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythensis, and Treponema denticola.[1],[2] The current research states that dysbiosis, as a result of these keystone pathogens, is primarily responsible for periodontitis (polymicrobial synergy dysbiosis model) and the vice versa too are hypothesized (inverted model).[3],[4]

Periodontal immunology

The gingiva and its defense mechanisms play a vital role in imparting immunity against bacterial colonization by preventing the breach of pathogens into the periodontium, and by the secretion of immunobiological components.[5] In addition, the physiological inflammatory response is initiated through a series of cellular and molecular networks framed by the epithelial cells, phagocytes, and complementary cascades. However, when the inflammation exceeds the physiological limits, T-cells, B cells, immunoglobulins, and other molecules play a role in presenting the antigen.[6] The activated acquired immunity with a help of a variety of biological mediators curb the inflammatory reactions by eliminating the pathogens. Thus, several pro-and anti-inflammatory mediators are triggered. When pro-inflammatory responses supersede the anti-inflammatory responses, immune tolerance arises.


   T-Cell and its Subsets Top


Based on function, T-cells are classified as the helper T-cells, killer T-cells, and memory T-cells, and also classified as CD4 and CD8 cells, considering their surface expression. The CD8 T-cells are the immune effector cells and are also called the cytotoxic T-cells, while CD4 T-cells are the helper cells (Th). Based on the cytokine production, they are further grouped [Figure 1] into subsets as Th1, Th2, Th17, and Tregs.[7] When the naive CD4 T-cells are encountered by the antigen presenting cells, they are differentiated into one of the subsets by producing the characteristic cytokines. While Th1 subsets impart a cell-mediated pro-inflammatory response, the Th2 subsets impart an antibody-mediated anti-inflammatory response. On the other hand, the Th17 (the effectors) and Treg (the regulators) subsets have a pivotal antagonistic role.[8]
Figure 1: Development of T cells. Th – T helper cells; Treg – T regulators; T cell – Thymus cell; B cell – Bursa of fabricius cell; CD4 – Cluster of Differentiation 4; CD8 – cluster of Differentiation 8; nTREG – Naturally occurring regulatory T cells; iTREG – Induced regulatory T cells

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Under noninflammatory healthy conditions, the homeostasis is maintained between the host and the commensal bacteria in the periodontium by the generation of regulatory T-cells. The antigen presenting cells favor the activation of Th2 cells that further trigger anti-inflammatory reactions. When dysbiosis occurs, they favor the activation of Th1 cells thereby promoting pro-inflammatory processes resulting in tissue damage.[9]


   Regulatory T-Cells Top


Tregs are polarized subpopulation of T lymphocytes regularizing immune activation and immune tolerance. They are characterized by the expression of Forkhead Box Protein 3 (foxP3) gene, which is potential enough to suppress the pro-inflammatory cytokines.[10] Tregs are of two types [Figure 1] namely, natural Tregs or nTregs (CD4+ CD25+ FoxP3+ cells) and induced Tregs or iTregs. The natural naive Tregs, which originates and matures from the thymus (intrathymic Tregs) produce a series of anti-inflammatory cytokines. On the contrary, the maturation of iTregs occurs peripherally. The iTregs are further grouped as Tr1 subset and Th3 subset based on their pattern of cytokine production. The Tr1 subset produces interleukin 10 (IL-10) and suppresses the Th1-mediated responses and the Th3 subset produces transforming growth factor beta (TGF-β) and has a regulatory function.[11]

Brief history

It was in the 1970s, where a suppressive subpopulation of T lymphocytes was suggested in animal models.[12] However, in 1995, Shimon Sakaguchi distinguished the suppressive subsets from regulatory subsets which were characterized as CD4 T cells that expressed both IL2Rαchain and CD25.[13] The suppressor subsets were then characterized to be self-reactive and were responsible for the development of autoimmune and inflammatory diseases.[14] Since then, Tregs have been through various bioassays and trials and their functions diversified with every discovery.

Their role in immune reactions

The paramount function of CD4+ CD25+ foxP3+ regulatory T-cells is to curtail the activation and the production of pro-inflammatory cytokines of the effector cells [Figure 2]. Besides the natural Tregs, the peripheral nonlymphoid tissue Tregs are found in the visceral adipose tissues, skeletal and cardiac muscles, mucosal interface, and hair follicles, that are all responsible for maintaining host-microbe homeostasis.[15],[16]
Figure 2: Treg activation , anti-inflammatory cytokine production and downregulation of pro-inflammatory cytokine. Th – T helper; TGF-β- Transforming growth factor β; IL-17- Interleukin 17; CTLA- Cytotoxic T lymphocyte associated molecule; TREG – Regulatory T cells; CD – Cluster of Differentiation ; IL – Interleukins; TH – T helper cells; ALP – Alkaline phosphatase; TGFB - Transforming growth factor beta

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   Tregs in Periodontitis Top


Tregs are characterized by the expression of the phenotypic markers such as transcription factor forkhead box P3 (FOXp3), CD103, glucocorticoid-inducible TNF receptor (GITR), inhibitory molecule cytotoxic T-lymphocyte-associated molecule 4 (CTLA-4), and cell-surface TGF-β1. Immunohistology, flow cytometry, and molecular analyses characterized the presence of these markers in periodontal tissues. TGF-β1 and the CTLA-4 were known to abate the progression of periodontitis.[17]

However, the RANKL inducing Th17 cells were also found to exceed in number, exacerbate inflammation in the periodontium and intensify bone loss.[18] Th17 cells are characterized by the expression of IL-17A and RORC2, that are the key factors aggravating inflammation and bone destruction[19] with the plasticity between Tregs and Th17 cells determining the nature of the immune response. Furthermore, P. gingivalis infection was found to promote Th17/Treg imbalance by influencing T-cell differentiation.[20]

Low Treg counts and suppressor function often accompany Th17-mediated autoimmunity, propagating inflammation and tissue destruction due to the Treg/Th17 cells imbalance.[21] The Treg/Th17 ratio was found to gradually increase in experimental periodontitis induced in rats, from 0 to 8 weeks and the ratio was significantly increased in the peripheral circulation in various stages of periodontitis. In the 12th week, the number of Treg cells was higher than Th17 cells, thereby decreasing the ratio. However, the balance waved through the course of periodontitis may be correlated with the progression of the disease and the pathological tissue damage.[22] On the contrary, Treg/Th17 imbalance was interpreted to be due to the lower Treg cell distribution in the human peripheral blood, and a higher number of Th17 cells in chronic periodontitis patients when compared to normal healthy controls. They also corresponded this observation to the conversion of Treg cells to pro-inflammatory phenotypes predominantly as Th17 cells due to a continuous low grade systemic inflammatory state.[23],[24] Thus, from these findings, it may be elucidated that when a large number of Tregs infiltrate into inflammatory sites, their peripheral count is reduced, and at the site of the inflammation, Th17 cells seem to comparatively outnumber Tregs cells. Moreover, when Treg function was inhibited using anti-GITR in mice with induced experimental periodontitis, there was increased inflammatory cell migration and alveolar bone loss.[25]


   Tailoring Tregs to Treat Periodontitis Top


Tregs are now being effectively used to prevent graft rejection, type 1 diabetes mellitus, lupus and auto-immune hepatitis due to their ability to be manipulated for adoptive-transfer purposes. Besides this, because of their immunosuppressive capabilities, they are used in immunotherapy. A group of systemically or locally delivered molecules such as cytokines, rapamycin, all trans-retinoic acid (ATRA), Vitamin D, and controlled Treg delivery systems[26] are used to promote the proliferation, availability, functional, and phenotype stability.

In a study, ATRA, the most active metabolite of Vitamin A, was administered orally every other day in experimental periodontitis-induced mice. ATRA was shown to increase the differentiation of naive T-cells to Tregs, downregulate IL-17 expression, and upregulate IL-10 and TGF-β1, thus reducing alveolar bone resorption.[27] In yet another study, Poly l-lactic acid (PLLA), nanofibrous spongy microspheres (NF-SMS), PLLA/polyethylene glycol (PEG) co-functionalized mesoporous silica nanoparticles (MSN), and poly lactic acid-co-glycolic acid microspheres (PLGA MS) were integrated and delivered as one vehicle for in situ Treg manipulation in a mouse model with periodontitis. MSNs and PLGA MS were shown to release miR-10a, essential for recruiting T-cells and IL-2/TGF-β1, essential for the differentiation of T cells into Tregs, while PLLA NF-SMS served as an injectable scaffold for the adhesion and proliferation of Treg cells. Thus, the system enriched the Treg cell-mediated immunity against alveolar bone loss.[28] Usually, when the corresponding ligand, endogenous CCL22 binds with the receptor, chemoattraction, and active migration occur. Based on this concept, CCL22 releasing formulations when injected into murines and canines with induced experimental periodontitis, an increased migration of Treg cells to the site of inflammation occurs, thereby suppressing associated bone loss. Such a formulation would include IL-4, which is a Th2 chemokine, along with biodegradable polymers like PLGA for tuned release behavior. Once introduced, IL-4 promotes CCL22 expression and Treg cell migration and upregulates Th2 response.[29],[30] Such an interaction was even tested in recent studies and the CCL22/CCR4/IL-A axis was found to have a strong inhibitory response to the pro-inflammatory mediators, preventing their production and migration to the inflammatory site.[29] Similarly, a mixture of factors such as IL-2, TGF-β, and rapamycin was effective in Treg induction at the sites of autoimmunity.[31]

Treg cell therapies are proved to be one of the promising regenerative therapies for both hard and soft tissues by upregulating the pro-regenerative factors such as BMP4, BMP7, RUNX2, ALP, DMP1, and COL1A1.[32] The availability of Tregs could be improved by culturing Dental Pulpal-Mesenchymal Stem Cells in vitro. The stem cells aid in the pooling of Tregs and enhancing immune homeostasis.[33] In addition, an altered neutrophil rheostat could be beneficial, as both an increase and decrease of neutrophils can lead to a progressive IL-17-mediated inflammatory response.[34] Although animal studies have shown desired results, the functional efficacy of Treg cell therapy to treat periodontitis in humans is yet to be explored.


   Future Directions of Tregs in Periodontics Top


Among the CD4+ Treg cells, CD69+ Treg cells, a newer subset, was discovered recently and their percentage was inversely correlated with periodontal attachment loss. However, their counts were found to be increased in gingival tissues than in the peripheral blood.[35] This could open a new avenue of therapy based on CD69+ Tregs. Another advent in Treg cell research is the expression of TNFR2 receptor, which has a tissue protective role mediated by Treg cells.[36],[37] Treg cytokine drugs like Tamibarotene (Am80) were found to reduce the osteoclast count, thereby decreasing the alveolar bone resorption.[38]

Numerous vaccines are being developed against periodontal infections. One such vaccine is based on a heat shock protein, peptide 19, which was shown to stimulate CD4+ CD25+ FoxP3+ cells, thereby suppressing autoimmunity.[39] The novel epitope spreader Pep19, could be targeted by human naive CD45RA+ Tregs for enhancing the expression of Tregs and their functions over effector T-cells by a process called linked suppression. Thus, Pep19-specific Tregs could be an effective molecular target for developing antigen-specific vaccinations to treat periodontitis.[40] Heat shock protein 60 was also found to be beneficial in upregulating Tregs.[41] Yet another study in mice with subcutaneous vaccination of P. gingivalis demonstrated a down regulation of Th17 cells and IL-17 A, thereby enhancing the action of Treg, RANKL + CD4+T cells, IL-10 and TGF-β1 production, resulting in a suppression of alveolar bone inflammation and destruction.[42]

Adoptive cell therapy in combination with RNA-guided nuclease technology has strengthened and stabilized Treg-cell base cell therapies for various autoimmune diseases such as rheumatoid arthritis. This insight is developed using clustered regularly inter-spaced short palindromic repeats in combination with Cas 9 (an RNA-guided DNA enodonuclease enzyme) system. This system is promising to be a high-throughput technology to manufacture Chimeric Antigen Receptor Tregs to cure autoimmune diseases.[43] This again may prove to be a new treatment option for periodontitis.

There is yet another entity of resident Treg cells in the gingival tissues, the CD8+ T cells, which are also gaining significance in suppressive immune responses. Future expanded studies and animal models with CD8+ cells may broaden their utility in immune therapy.[44] A study on mice suggested that CCL22 when locally administered into the root canals, helped in regression of periapical lesion by manipulating chemoattraction of Tregs through CCL22/CCR4 axis, reducing the pro-inflammatory mediators.[45]

Another novel approach would be modifying the migration of Treg cells for a targeted delivery by altering their homing capacity, proven by a study conducted on mice with intestinal inflammation by injecting specific homing-receptors, targeting Th1 inflamed sites.[46]


   Limitations in Treg Therapy Top


Despite the huge number of literature supporting the stability, yield and plasticity of Tregs generated in vitro, there is a lack of data on human trials. Major factors hindering such advancements could be the cost and the risks involved in these cell-based therapies, since they are in their nascent state of discoveries and developments. Human-based trials and further modifications to maintain their stability in vivo would encourage cell therapies to serve as a promising treatment for periodontitis.


   Conclusion Top


With the advantages of cell therapies, Treg cell therapy would be a potent futuristic treatment option to address and treat periodontitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Abstract
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    Future Direction...
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