γδT cells in oral tissue immune surveillance and pathology

Abstract

The oral mucosa's immune system is composed of tissue-resident and specifically recruited leukocytes that could effectively tolerate a wide range of microbial and mechanical assaults. Shortly after CD4⁺ helper T cells (TH17 cells) that produce interleukin 17 (IL-17) were identified, it was discovered that γδT cells could also induce substantial levels of this pro-inflammatory cytokine. In the past decades, it has become clear that due to a complicated thymic program of development, γδT cells frequently serve as the primary sources of IL-17 in numerous models of inflammatory diseases while also assisting in the maintenance of tissue homeostasis in the skin and intestine. But it wasn't until recently that we took thorough insight into the complex features of γδT cells in the oral mucosa. Most gingival intraepithelial γδT cells reside in the junctional epithelium adjacent to the dental biofilm, suggesting their potential role in regulating oral microbiota. However, inconsistent results have been published in this regard. Similarly, recent findings showed contradictory data about the role of γδT lymphocytes in experimental periodontitis based on different models. In addition, conflicting findings were presented in terms of alveolar bone physiology and pathology underlying the oral mucosa. This review provided an overview of current knowledge and viewpoints regarding the complex roles played by oral-resident γδT cells in host-microbiota interactions, gingivitis and periodontitis, bone physiology and pathology.

Keywords: bone remodeling; microbiota; oral mucosa; periodontitis; γδT cells.

Figure 1

Functional and distributional characterization of murine Vγ1⁺, Vγ4⁺, Vγ5⁺, Vγ6⁺, and Vγ7⁺ γδT cells subsets. IL-17 production is mainly restricted to Vγ4⁺ or Vγ6⁺ γδT cell subsets while Vγ1⁺, Vγ5⁺, and Vγ7⁺ γδT cells are associated with the secretion of IFN-γ. Different surface receptors that IL-17+and IFN-γ+ γδT cell subsets express allow for their identification and isolation. γδ17T cells express IL-1R, IL-23R, IL-7R, CCR2, CCR6, and CD44 on the cell surface, and the transcriptional factors of RORγt, Blk, Hes-1, Sox4, and Sox13 are important for γδ17T cells development and function. IFN-γ-producing γδT cells, on the other hand, exhibit cell surface markers CD27, CD122, and NK1.1 (8). They selectively home to various organs, and serve important functions in tissue immune surveillance and homeostasis.

Figure 2

The interplay between γδ17T cells and microbiota in the oral mucosa. Gingival γδT cells are mainly located in the junctional epithelium and the lamina propria and are primarily composed of Vγ6⁺, Vγ1⁺, and Vγ4⁺ subsets. The Vγ5⁺ and Vγ7⁺ subgroups can also be found in the gingiva, albeit at much lower frequencies. During embryogenesis, Vγ6⁺ and Vγ5⁺ γδT cells develop in the embryonic thymus and reach the oral mucosa during embryogenesis, while Vγ1⁺ and Vγ4⁺ develop in both embryonic and adult thymus. Over the suckling and weaning period, the Vγ6⁺ subset expands locally in a microbiota-dependent manner, whereas the Vγ4⁺ and Vγ1⁺ subsets arrive at the oral mucosa via circulation. Most mice gingival γδT cells express Vγ6⁺ TCR-chain and have a preactivated phenotype representing the main IL-17–producing lymphocyte subset in oral tissues. Under the constant challenge of physical stress and pathogen invasion, specific cytokines and pathogens stimulation can promote the growth and proliferation of γδ17T cells. Activated γδ17T cells then recruit neutrophils to the junctional epithelial site by IL-17 signaling and protect against oral pathogens.

Figure 3

Three different γδT cell loss-of-function mouse models. The images show the characteristics of the three different mouse models and their respective relevant experimental results.

Figure 4

The role of γδ17T cells in oral bone physiology and pathology. γδT cell depletion in steady-state using Tcrd-GDL mice (Top bar). No increased alveolar bone loss was discovered after the DT injection. However, a decline in osteoclast levels around the alveolar bone was detected implying the likely function of γδT cells in controlling osteoclast formation. The absence of an overall effect on alveolar bone may be result from the suppression of osteoblasts activity or a greater activation of osteoclasts. In the jaw osteonecrosis model (middle bar), instead of quantity, γδT cells have an impact on the osteoclasts’ distribution on the palatal surface after tooth extraction. In the movement of orthodontic teeth (bottom bar), as the major source of IL-17A in the PDL, γδT cells could upregulate RANKL expression by PDL fibroblasts (103), recruit neutrophil and monocytes, and therefore facilitate osteoclast formation and subsequently bone resorption in the pressure site during OTM.