Treg: A Promising Immunotherapeutic Target in Oral Diseases

Abstract

With the pandemic of COVID-19, maintenance of oral health has increasingly become the main challenge of global health. Various common oral diseases, such as periodontitis and oral cancer, are closely associated with immune disorders in the oral mucosa. Regulatory T cells (Treg) are essential for maintaining self-tolerance and immunosuppression. During the process of periodontitis and apical periodontitis, two typical chronic immune-inflammatory diseases, Treg contributes to maintain host immune homeostasis and minimize tissue damage. In contrast, in the development of oral precancerous lesions and oral cancer, Treg is expected to be depleted or down-regulated to enhance the anti-tumor immune response. Therefore, a deeper understanding of the distribution, function, and regulatory mechanisms of Treg cells may provide a prospect for the immunotherapy of oral diseases. In this review, we summarize the distribution and multiple roles of Treg in different oral diseases and discuss the possible mechanisms involved in Treg cell regulation, hope to provide a reference for future Treg-targeted immunotherapy in the treatment of oral diseases.

Keywords: Treg; immunotherapy; oral cancer; oral diseases; periodontitis.

Figure 1

Immune regulatory functions of Treg cells in apical periodontitis and periodontitis. Treg cells inhibit the differentiation of osteoclast precursors into osteoclasts by secreting inhibitory cytokines, such as IL-10, IL-4, and TNF-β. Also, inhibiting receptor cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) on Treg cells directly in contact with osteoclast precursors costimulatory molecules CD80 and CD86, which can induce the production of indoleamine 2,3-dioxygenase (IDO) and induce the apoptosis of osteoclast precursors. Th17 cells upregulate osteoblasts and self-expressed receptor activator of nuclear factor kappa B ligand (RANKL) through the release of inflammatory cytokine IL-17. At the same time, IL-17 plays an important role in the mobilization and recruitment of immune cells, stimulating the release of local inflammatory factors, resulting in the expansion of osteoclasts, and the aggravation of inflammatory response. Pre-OC, osteoclast precursors; RANK, the receptor activator of nuclear factor kappa B.

Figure 2

Distribution and functions of Treg cells in head and neck squamous cell carcinoma. (A) Treg cells increase during the disease progression in oral mucosal dysplasia and squamous cell carcinoma. Malignant cells can secret CCL22 to attract Treg cells, or secret TGF-β to suppress inflammatory Th17 cells. (B) Immune suppressive mechanisms of Treg cells in head and neck squamous cell carcinoma. Treg cells can secret inhibitory cytokines, such as TGF-β, IL-10, and IL-35, to suppress the functions of antigen-presenting cells (APC) and CD8⁺ effector T cells, directly kill effector or APC by granzymes, consume of IL-2 by highly expressing CD25, and negatively regulate the maturation and functions of APC by immune checkpoint molecules, such as LAG-3 and CTLA4.

Figure 3

Regulatory mechanisms of Treg cells recruitment, proliferation, and function in oral diseases. Macrophages and antigen-presenting cells upregulate the release of cytokine C-C motif ligand 22 (CCL22) in an inflammatory environment and recruit more Treg cells to local tissues in a CC-chemokine receptor 4 (CCR4) dependent manner. Similarly, tumor cells are involved in the release of CCL22 in head and neck cancer. In addition, the binding of IL-2 and its receptor CD25 activated the JAK/STAT5 signaling pathway to induce FOXP3 expression. Transforming growth factor β (TGF-β) also has a positive effect on FOXP3 expression by activating mothers against decapentaplegic homologue 3 (SMAD3) transcription factors. Besides, IL-33 binds to the IL-1 receptor-like 1 (ST2) and further promotes the expression of FOXP3 and proliferation of Treg cells. The PI3K-Akt-mTOR pathway activated by inflammatory Toll-like receptor (TLR) or T cell receptor (TCR) signals may be involved in the FOXP3 expression inhibition and the regulation of Treg proliferation, while FOXP3 can negatively feedback on Akt activation. Post-translational modification of mature FOXP3 protein, such as acetylation, enhances both stability and activity of FOXP3. FOXP3 can endow Treg with typical characteristics, such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR). APC, antigen-presenting cells; CNS, conserved non-coding sequence; IL-2R, IL-2 receptor; LPS, lipopolysaccharide; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; JAKs, Janus kinases; STAT5, signal transducer and activator of transcription 5; PI3K, phosphoinositide 3-kinase; mTOR, mammalian target of rapamycin; TGF-βR, TGFβ receptor; TLR, Toll-like receptor.