Regulatory T Lymphocytes in Periodontitis: A Translational View

Abstract

Periodontitis is a chronic immuno-inflammatory disease in which the disruption of the balance between host and microbiota interactions is key to the onset and progression of the disease. The immune homeostasis associated with periodontal health requires a regulated immuno-inflammatory response, during which the presence of regulatory T cells (Tregs) is essential to ensure a controlled response that minimizes collateral tissue damage. Since Tregs modulate both innate and adaptive immunity, pathological conditions that may resolve by the acquisition of immuno-tolerance, such as periodontitis, may benefit by the use of Treg immunotherapy. In recent years, many strategies have been proposed to take advantage of the immuno-suppressive capabilities of Tregs as immunotherapy, including the ex vivo and in vivo manipulation of the Treg compartment. Ongoing research in both basic and translational studies let us gain a better understanding of the diversity of Treg subsets, their phenotypic plasticity, and suppressive functions, which can be used as a substrate for new immunotherapies. Certainly, as our knowledge of Treg biology increases, we will be capable to develop new therapies designed to enhance the stability and function of Tregs during periodontitis.

Figure 1

Treg suppressive functions. Tregs have several suppressive mechanisms that may inhibit different cell types. For instance, Tregs can directly inhibit antigen-presenting cells (APCs), such as dendritic cells (DCs), through its inhibitory receptor CTLA-4 that bounds to the costimulatory molecules CD80 and CD86, expressed on the surface of APCs. This interaction induces the production of indoleamine 2,3-dioxygenase (IDO), which in turn may provoke apoptosis of DCs and preosteoclasts. In addition, CTLA-4 competes with the CD28 receptor present on the surface of effector T cells (Teff) and inhibits costimulatory signals during antigenic presentation. Similarly, CTLA-4 directly suppresses osteoclast differentiation and activation, mechanisms potentiated by the secretion of inhibitory cytokines such as IL-4, IL-5, IL-10, TGF-β, and GM-CSF. Furthermore, Tregs suppress the pro-inflammatory functions of Teff, such as Th17 (CD4⁺ RORC2⁺) lymphocytes through various mechanisms such as the local consumption of IL-2; secretion of anti-inflammatory cytokines such as IL-10, IL-35, and TGF-β; inhibition of antigenic presentation; transformation of ATP and ADP to adenosine by surface ectoenzymes (CD39 and CD73), and the controlled release of perforin and granzyme. Finally, Tregs may promote tissue repair through the production of amphiregulin (AREG), ligand of the epidermal growth factor receptor (EGFR), expressed in epidermal cells and other resident cells.

Figure 2

Therapeutic approaches for Treg enrichment in vivo. There is an array of systemically or locally delivered molecules that may promote Treg proliferation, phenotype stability, and functionality in vivo. Among them, IL-2 has been described as a major growth factor for T cells, particularly important for Treg physiology. IL-2 binds to its receptor CD25, whose signaling pathway induces Foxp3 expression on Tregs and inhibits Th17 differentiation. Foxp3 enables the expression of canonical Treg features, such as CTLA-4, GITR, and anti-inflammatory cytokines. On the other hand, all-trans retinoic acid (atRA) and calcitriol (VitD₃), active metabolites of vitamins A and D, have shown to reinforce suppressive functions of Tregs. atRA induces the binding of the RA receptor (RAR) and the retinoic X receptor (RXR) to an intronic enhancer of foxp3 gene locus, increasing its expression. Similarly, VitD₃ binds to the vitamin D receptor (VDR), which later binds to RXR, forming a heterodimer that translocates towards the nucleus to promote Foxp3 expression. Also, VitD₃ induces tolerogenic dendritic cells (DC Tol), with an immature phenotype that may drive Treg responses. Rapamycin (RAPA) inhibits mTOR signaling pathway, allowing preferential expansion of Tregs, and blocks critical Teff functions. Additionally, IL-33 binds to ST2 receptor, promoting further Foxp3 and ST2 expression on Tregs. Also, indirectly, IL-33 supports Treg expansion, inducing IL-2 secretion by myeloid cells, which stimulates additional ST2 expression. Finally, CCL22-loaded nanoparticles may recruit CCR4⁺ Tregs locally, decreasing Teffs and their pro-inflammatory functions.