Natural Killer T (NKT) Cells and Periodontitis: Potential Regulatory Role of NKT10 Cells

Abstract

Natural killer T (NKT) cells constitute a unique subset of T lymphocytes characterized by specifically interacting with antigenic glycolipids conjugated to the CD1d receptor on antigen-presenting cells. Functionally, NKT cells are capable of performing either effector or suppressor immune responses, depending on their production of proinflammatory or anti-inflammatory cytokines, respectively. Effector NKT cells are subdivided into three subsets, termed NKT1, NKT2, and NKT17, based on the cytokines they produce and their similarity to the cytokine profile produced by Th1, Th2, and Th17 lymphocytes, respectively. Recently, a new subgroup of NKT cells termed NKT10 has been described, which cooperates and interacts with other immune cells to promote immunoregulatory responses. Although the tissue-specific functions of NKT cells have not been fully elucidated, their activity has been associated with the pathogenesis of different inflammatory diseases with immunopathogenic similarities to periodontitis, including osteolytic pathologies such as rheumatoid arthritis and osteoporosis. In the present review, we revise and discuss the pathogenic characteristics of NKT cells in these diseases and their role in the pathogenesis of periodontitis; particularly, we analyze the potential regulatory role of the IL-10-producing NKT10 cells.

Figure 1

Antigenic presentation and activation of NKT cells. During antigen presentation, NKT cells recognize, via their TCR, the glycolipid antigen conjugated to the CD1d receptor expressed by antigen-presenting cells. In this context, the costimulatory ligand/receptor interactions between OX40L/OX40, CD80/CD28, and IL-12/IL-12R promote the activation of the transcription factors NF-AT, NF-κB, and T-bet. In turn, these activations lead to the production of IL-2 and survivin, which promote NKT cell proliferation and survival by activation of the PI3K-PDK1-AKT signaling pathway. Furthermore, the CD40/CD40L interaction promotes the activation of NF-κB in antigen-presenting cells, which induces IL-12 and CD80 production and promotes the CD4⁺ and CD8⁺ T lymphocyte activation and proliferation. AKT, protein kinase B; CD, cluster of differentiation; IL, interleukin; NF-AT; nuclear factor of activated T cells; NF-κB, nuclear factor κB; NKT, Natural Killer T cell; OX40, tumor necrosis factor receptor superfamily member 4; OX40L, tumor necrosis factor receptor superfamily member 4 ligand; PDK1, pyruvate dehydrogenase lipoamide kinase isozyme 1; PI3K, phosphatidylinositol-3-kinase; T-bet, transcription factor T-box; TCR, T-cell receptor. (Created with http://biorender.com).

Figure 2

Maturation and differentiation of NKT cells. (a) According to the linear maturation model, mice NKT cells go through four maturation stages, from S0 to S3. After antigen presentation, NKT cells progress from an immature stage S0 as CD24⁺CD44⁻NK1.1⁻ cells to stage S1 as IL-4-producing CD24⁻CD44⁻NK1.1⁻ cells, depending on the activation of transcription factors PLZF and GATA3. After activation of the transcription factor RORγt, cells mature to stage S2 as CD24⁻CD44⁺NK1.1⁻ cells, which also produce IL-4. Finally, activation of the transcription factor T-bet promotes maturation to state S3 as CD24⁻CD44⁺NK1.1^-/+ cells, which produce IFN-γ. (b) After the antigenic presentation, NKT0 EGR2⁺CD24⁺CD44⁻NK1.1⁻ progenitor cells differentiate to CD4⁺IL17RB⁻ precursor cells in a manner dependent on the activation of the transcription factor PLZF. After the activation of the transcription factors T-bet, GATA3, RORγt, or E4BP4, the precursor NKT cells acquire the potential to differentiate into IFN-γ-producing NKT1 T-bet⁺CD122⁺IL17RB⁻, IL-4-producing NKT2 GATA3⁺CD4⁺CD27⁺IL17RB⁺, IL-17A-producing NKT17 RORγt⁺CD4⁻CD27⁻IL17RB^+/-, or IL-10-producing NKT10 E4BP4⁺CD152⁺NK1.1⁺ cells. APCs, antigen-presenting cells; CD, cluster of differentiation; EGR2, early growth response protein-2; E4BP4, transcription factor E4 promoter-binding protein 4; GATA3, transcription factor GATA binding protein 3; IFN, interferon; IL, interleukin; NK1.1, Natural Killer cell pectin-like receptor subfamily B molecule member 1; NKT, Natural Killer T cell; NKTp, Natural Killer T cell precursor; NKT0, Natural Killer T cell progenitor; PLZF, promyelocytic leukemia zinc finger; RORγt, transcription factor retinoic acid-related orphan nuclear receptor γt; T-bet, transcription factor T-box; TCR, T-cell receptor. (Created with http://biorender.com).

Figure 3

Distribution of NKT cells during their maturation in the mice thymus. During their maturation process, the NKT precursor cells located in the thymic cortex migrate towards the medulla to maturate and acquire the phenotypes NKT1, NKT2, or NKT17. In the thymic medulla, steady-state NKT2 cells produce IL-4 and promote the activation of medullar thymocytes. Conversely, NKT1 and NKT17 cells return to the cortical area. IL, interleukin; NKT, natural killer T cell; NKTp, Natural Killer T cell precursor. (Created with http://biorender.com).

Figure 4

NKT cell-mediated transactivation. Following antigen presentation, NKT cells rapidly produce high levels of IFN-γ or IL-4. IFN-γ-producing NKT1 cells promote the lytic activity of CD8⁺ lymphocytes and NK cells and the production of IgE and IgG in B lymphocytes. On the other hand, IL-4-producing NKT2 cells promote the production of IL-12 and IL-18 in APCs, the production of IgE and IgG in B lymphocytes, and the production of IFN-γ and capacity for specific antigen recognition in CD4⁺ T lymphocytes. APCs, antigen-presenting cells; CD, cluster of differentiation; IFN, interferon; Ig, immunoglobulin; IL, interleukin; NK, Natural Killer cell; NKT, Natural Killer T cell; TCR, T-cell receptor. (Created with http://biorender.com).

Figure 5

Role of NKT cells during periodontal health and disease. During periodontal health, the low-grade antigenic load of commensal microbial origin favors the differentiation and activity of NKT2 cells and eventually NKT10 cells. In this context, NKT2 and NKT10 cells could promote the transactivation of Th2 and Treg lymphocytes, which inhibit osteoclastogenesis and M1 macrophage activation, and induce osteoblastogenesis and M2 macrophage activation, thus favoring periodontal tissue homeostasis. During periodontitis, the host's immune response is triggered against the dysbiotic bacterial communities colonizing the subgingival environment. During this process, the antigen-presenting cells present the microbial and tissue-damage antigens to the distinct immune effector cells; therefore, they can present antigens of a glycolipid nature to NKT cells. In this context, activated NKT cells acquire the potential to differentiate into NKT1 and NKT17 cells. Then, NKT1 and NKT17 cells could promote the transactivation of Th1 and Th17 lymphocytes, which induce the activation of M1 macrophages and the differentiation and function of osteoclasts, and consequently, promote periodontal inflammation and alveolar bone resorption. IFN, interferon; IL, interleukin; Treg, regulatory T lymphocytes; NKT, Natural Killer T cell; RANKL, receptor activator of nuclear factor κΒ ligand; TGF, transforming growth factor; TNF, necrosis factor tumors. (Created with http://biorender.com).