Helper T-cell response in periodontitis

Introduction

Periodontitis is a complex, chronic inflammatory disease that affects the supporting structures of the teeth, including the gingiva, periodontal ligament, and alveolar bone. It results from the interaction between microbial biofilms and the host’s immune response. Understanding the immune response in periodontitis is crucial for developing effective treatments and preventive strategies. A critical aspect of the immune response in periodontitis involves T cells, particularly helper T cells (Th cells). These cells play a significant role in modulating the immune response and influencing disease progression.

Innate Immune Response

The innate immune response is the first line of defense against periodontal pathogens. When pathogens invade the periodontium, the innate immune system is activated, leading to the recruitment of various immune cells to the site of infection.

Neutrophils

Neutrophils are among the first immune cells to arrive at the site of infection. They play a critical role in controlling bacterial invasion through phagocytosis and the release of antimicrobial peptides. However, an excessive neutrophil response can lead to tissue damage and contribute to the progression of periodontitis.

Macrophages

Macrophages are versatile immune cells that can adopt different functional states, such as M1 (pro-inflammatory) and M2 (anti-inflammatory). In periodontitis, M1 macrophages are predominant and contribute to inflammation and tissue destruction by releasing pro-inflammatory cytokines like TNF-α, IL-1β, and IL-62. M2 macrophages, on the other hand, are involved in tissue repair and resolution of inflammation.

Dendritic Cells

Dendritic cells (DCs) are antigen-presenting cells that play a crucial role in bridging the innate and adaptive immune responses. In periodontitis, DCs capture and process bacterial antigens, presenting them to T cells and initiating the adaptive immune response.

Adaptive Immune Response

The adaptive immune response is characterized by the activation of specific lymphocytes, including T cells and B cells, which provide a more targeted and sustained response to periodontal pathogens.

T Cells

T cells are central to the adaptive immune response in periodontitis. Different subsets of T cells, including CD4+ helper T cells and CD8+ cytotoxic T cells, are involved in the immune response.

CD4+ Helper T Cells: These cells can differentiate into various subsets, such as Th1, Th2, Th17, and T regulatory (Treg) cells. Th1 cells produce pro-inflammatory cytokines like IFN-γ, which activate macrophages and enhance their bactericidal activity. Th17 cells produce IL-17, which recruits neutrophils and contributes to inflammation4. Treg cells, on the other hand, help regulate the immune response and prevent excessive inflammation.

CD8+ Cytotoxic T Cells: These cells are involved in the direct killing of infected cells. In periodontitis, CD8+ T cells can contribute to tissue damage by releasing cytotoxic molecules like perforin and granzyme5.

B Cells and Plasma Cells

B cells are responsible for the production of antibodies, which can neutralize pathogens and facilitate their clearance. In periodontitis, B cells can differentiate into plasma cells that produce antibodies against periodontal pathogens. Elevated levels of plasma cells and antibodies are often observed in periodontitis tissues

Helper T Cells: Classification and Function

Helper T cells are a subset of T lymphocytes that play a pivotal role in orchestrating the immune response. They are classified into several subtypes based on their cytokine profiles and functions:

Th1 Cells: Produce interferon-gamma (IFN-γ) and are involved in cell-mediated immunity, enhancing the activity of macrophages and cytotoxic T cells.

Th2 Cells: Produce interleukins (IL-4, IL-5, IL-13) and are associated with humoral immunity, promoting B cell differentiation and antibody production.

Th17 Cells: Produce IL-17 and IL-22, playing a crucial role in neutrophil recruitment and inflammation.

T Regulatory Cells (Tregs): Produce IL-10 and transforming growth factor-beta (TGF-β), involved in maintaining immune tolerance and preventing excessive immune responses.

Th1 Cell genesis and functions

Th1 cells, a subset of CD4+ T helper cells, play a crucial role in the immune response against intracellular pathogens such as viruses and certain bacteria. Their development and function are tightly regulated by a series of signals and interactions. Th1 cells originate from common T cell progenitors in the thymus. These progenitors undergo a series of developmental stages, including double-negative (CD4- CD8-) and double-positive (CD4+ CD8+) phases, before differentiating into single-positive CD4+ T cells. Positive and negative selection processes in the thymus ensure that only T cells with appropriate T cell receptors (TCRs) survive. This selection is crucial for the development of a functional and self-tolerant T cell repertoire. Naive CD4+ T cells are activated in peripheral lymphoid organs upon encountering antigen-presenting cells (APCs) such as dendritic cells. These APCs present antigens via MHC class II molecules and provide co-stimulatory signals necessary for T cell activation. The differentiation of activated CD4+ T cells into Th1 cells is driven by the cytokine environment. Key cytokines involved include IL-12 and IFN-γ, which are produced by APCs and other immune cells. The transcription factor T-bet is critical for Th1 differentiation. T-bet promotes the expression of Th1-specific genes and suppresses the differentiation of other T helper cell subsets.

Functions of Th1 Cells

Th1 cells are primarily involved in cell-mediated immunity, which is essential for combating intracellular pathogens. Their functions include:

Cytokine Production:

IFN-γ: Th1 cells produce interferon-gamma (IFN-γ), a key cytokine that activates macrophages, enhancing their ability to phagocytose and kill intracellular pathogens.

TNF-α: Tumor necrosis factor-alpha (TNF-α) is another cytokine produced by Th1 cells. It plays a role in inflammation and helps recruit other immune cells to the site of infection.

Activation of Macrophages:

Th1 cells enhance the microbicidal activity of macrophages through the production of IFN-γ. This activation leads to the production of reactive oxygen species (ROS) and nitric oxide (NO), which are toxic to pathogens.

Support for Cytotoxic T Cells:

Th1 cells provide help to CD8+ cytotoxic T cells, promoting their differentiation and enhancing their ability to kill infected cells. This support is crucial for the clearance of intracellular pathogens.

Regulation of Immune Responses:

Th1 cells play a role in regulating the balance between different types of immune responses. By producing IFN-γ, they can inhibit the differentiation of Th2 cells, which are involved in humoral immunity.

Th2 Cell genesis and functions

Th2 cells, a subset of CD4+ T helper cells, play a pivotal role in orchestrating immune responses, particularly in the context of allergic reactions and defense against extracellular parasites. Th2 cell differentiation begins when naive CD4+ T cells encounter antigen-presenting cells (APCs) displaying antigens via MHC class II molecules. This interaction, along with co-stimulatory signals, activates the naive T cells. The presence of specific cytokines, particularly IL-4, is crucial for Th2 differentiation. IL-4 activates the transcription factor GATA3, which drives the expression of Th2-specific genes.

Transcription Factors:

GATA3: This transcription factor is essential for Th2 cell differentiation. It promotes the expression of Th2 cytokines and inhibits the differentiation of other T helper cell subsets2.

STAT6: Signal transducer and activator of transcription 6 (STAT6) is activated by IL-4 and works in conjunction with GATA3 to promote Th2 differentiation3.

Functions of Th2 Cells

Th2 cells are primarily involved in humoral immunity and play a significant role in allergic responses and defense against helminths.

Cytokine Production:

IL-4: Promotes B cell class switching to IgE, which is crucial for allergic responses. IL-4 also enhances the differentiation of Th2 cells and inhibits Th1 cell differentiation4.

IL-5: Stimulates the growth and activation of eosinophils, which are important for combating parasitic infections5.

IL-13: Shares many functions with IL-4, including promoting IgE production and contributing to mucus production in the airways.

Role in Allergic Responses:

Th2 cells are central to the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. They promote the production of IgE antibodies, which bind to allergens and trigger mast cell degranulation, leading to allergic inflammation.

Defense Against Helminths:

Th2 cells are crucial for the immune response against helminth infections. They promote the activation of eosinophils and mast cells, which release toxic granules that help eliminate parasites.

Tissue Repair and Remodeling:

Th2 cytokines, particularly IL-4 and IL-13, play a role in tissue repair and remodeling. They promote the activation of fibroblasts and the production of extracellular matrix components, which are important for wound healing.

Th17 Cell genesis and functions

Th17 cells are a subset of CD4+ T helper cells that play a crucial role in the immune response, particularly in defending against extracellular bacteria and fungi, as well as in the pathogenesis of autoimmune diseases. Th17 cell differentiation begins when naive CD4+ T cells encounter antigen-presenting cells (APCs) displaying antigens via MHC class II molecules. This interaction, along with co-stimulatory signals, activates the naive T cells. The differentiation of Th17 cells is driven by a specific cytokine milieu. Key cytokines involved include TGF-β, IL-6, IL-21, and IL-232. These cytokines are produced by APCs and other immune cells in response to pathogens.

Transcription Factors:

RORγt: The transcription factor retinoic acid receptor-related orphan receptor gamma t (RORγt) is essential for Th17 cell differentiation. It promotes the expression of Th17-specific genes3.

STAT3: Signal transducer and activator of transcription 3 (STAT3) is activated by IL-6 and IL-23 and works in conjunction with RORγt to drive Th17 differentiation4.

Functions of Th17 Cells

Th17 cells are primarily involved in the immune response against extracellular pathogens and play a significant role in inflammation and autoimmunity.

Cytokine Production:

IL-17A and IL-17F: These cytokines are the hallmark of Th17 cells. They induce the production of pro-inflammatory mediators such as IL-6, TNF-α, and chemokines, which recruit neutrophils to the site of infection5.

IL-21: This cytokine amplifies the Th17 response and promotes the differentiation of additional Th17 cells.

IL-22: IL-22 helps maintain the integrity of epithelial barriers and promotes the production of antimicrobial peptides.

Role in Autoimmunity:

Th17 cells have been implicated in the pathogenesis of several autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, and psoriasis. Their pro-inflammatory cytokines contribute to tissue inflammation and damage in these conditions.

Defense Against Pathogens:

Th17 cells are crucial for the defense against extracellular bacteria and fungi. They enhance the recruitment and activation of neutrophils, which are essential for clearing these pathogens.

Tissue Homeostasis:

Th17 cells play a role in maintaining mucosal barriers and promoting tissue repair. IL-22, in particular, is involved in the regeneration of epithelial cells and the production of protective mucus.

Treg Cell genesis and functions

Regulatory T cells (Tregs) are a specialized subset of T cells that play a crucial role in maintaining immune homeostasis and preventing autoimmune diseases. They are characterized by the expression of CD4, CD25, and the transcription factor FOXP3. Tregs originate from progenitor cells in the bone marrow and undergo differentiation in the thymus. These progenitors are initially double-positive (CD4+ CD8+) thymocytes. During thymic selection, Tregs are positively selected based on their ability to recognize self-antigens with intermediate affinity. This process ensures that Tregs can effectively suppress self-reactive T cells. The expression of FOXP3 is a defining feature of Tregs. FOXP3 is crucial for the development and function of Tregs, and mutations in the FOXP3 gene can lead to severe autoimmune diseases. In addition to thymus-derived natural Tregs (nTregs), Tregs can also be induced in the periphery from naive CD4+ T cells under specific conditions. This process is driven by cytokines such as TGF-β and IL-2.

Functions of Regulatory T Cells

Tregs are essential for maintaining immune tolerance and preventing excessive immune responses. Their functions include:

Suppression of Immune Responses:

Cytokine Production: Tregs produce anti-inflammatory cytokines such as IL-10 and TGF-β, which help suppress the activation and proliferation of effector T cells.

Cell-Cell Contact: Tregs can directly suppress other immune cells through cell-cell contact mechanisms involving molecules like CTLA-4 and LAG-3.

Maintenance of Immune Homeostasis:

Prevention of Autoimmunity: By suppressing self-reactive T cells, Tregs play a critical role in preventing autoimmune diseases. They help maintain tolerance to self-antigens and prevent immune-mediated tissue damage.

Regulation of Inflammation: Tregs help control the extent and duration of inflammatory responses, ensuring that inflammation is resolved once the pathogen is cleared.

Role in Cancer and Transplantation:

Cancer: Tregs can suppress anti-tumor immune responses, which can be detrimental in the context of cancer. High levels of Tregs in the tumor microenvironment are often associated with poor prognosis.

Transplantation: Tregs are beneficial in transplantation settings as they help prevent graft rejection by suppressing allo-reactive T cells.

Review of literature on Helper T cell response in periodontitis

As discussed in chapter 6 and 7, periodontitis is a chronic inflammatory disease that affects the supporting structures of the teeth. Among the key players in the immune response are Helper T (Th) cells, which are critical in orchestrating the immune response through cytokine production and interaction with other immune cells. Yamazaki et al. (2006) (References available in the book) investigated the Th1/Th2 balance in chronic periodontitis. The study observed a higher expression of Th1 cytokines (IFN-γ) in the gingival tissues of periodontitis patients compared to healthy controls. This Th1 dominance was associated with increased macrophage activation and tissue destruction. Gaffen and Hajishengallis (2008) investigated the Th1/Th2 paradigm in the context of periodontal disease. The review highlighted the complex interplay between Th1 and Th2 responses, suggesting that both Th1-mediated pro-inflammatory and Th2-mediated humoral responses contribute to periodontal tissue destruction and host defense.

Cardoso et al. (2009) evaluated the presence and role of Th17 cells in periodontal lesions. The study demonstrated increased levels of Th17 cells and IL-17 in the gingival tissues of periodontitis patients. The presence of Th17 cells correlated with disease severity and suggested a significant role for Th17-mediated inflammation in periodontal pathology. An animal model study by Takahashi et al. (2010) was intended to investigate the role of Th17 cells in experimental periodontitis. Using a murine model, the study found that IL-17-deficient mice exhibited reduced bone loss and inflammation in periodontal tissues, indicating that IL-17 and Th17 cells are crucial for disease progression.

Nakajima et al. (2005) examined the role of Tregs in periodontal disease. The study observed a decrease in Treg populations in periodontitis patients compared to healthy controls. The reduced Treg presence was associated with elevated pro-inflammatory cytokines, suggesting that impaired Treg function contributes to uncontrolled inflammation in periodontitis. In another study, Liu et al. (2011) investigated the therapeutic potential of Treg enhancement in periodontitis. The study showed that adoptive transfer of Tregs into periodontitis-induced mice led to a significant reduction in inflammatory markers and bone loss, highlighting the potential of Treg-based therapies for periodontal disease.

These studies collectively highlight the significant roles of various Th cell subsets, particularly Th1, Th2, Th17, and Tregs, in the pathogenesis of periodontitis. The complex interplay between these cells and their cytokine profiles underscores the importance of a balanced immune response in maintaining periodontal health and preventing disease progression.

Conclusion

The immune response in periodontitis involves a complex interplay between various T helper cell subsets. Th1, Th2, Th17, and Treg cells all contribute to the pathogenesis and progression of the disease through their distinct cytokine profiles and functions. Understanding the roles and interactions of these Th cell subsets is crucial for developing targeted therapies to modulate the immune response and improve periodontal health.

References

References are available in hardcopy of the website “Periobasics: A Textbook of Periodontics and Implantology”.