Helper T (Th) Cells
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About Helper T (Th) Cells
Helper T (Th) cells are a critical subset of immune cells that play a central role in orchestrating and regulating the immune response. They are a type of CD4+ T lymphocyte, expressing the CD4 protein on their cell surface. Th cells act as key intermediaries between innate and adaptive immunity by coordinating and modulating the functions of other immune cells.
Th cells recognize and respond to antigens presented by antigen-presenting cells (APCs) such as dendritic cells. Upon activation, Th cells undergo clonal expansion and differentiate into distinct subsets based on the signals they receive from APCs and the cytokine milieu. The major subsets of Th cells include Th1, Th2, Th9, Th17, Th22, and T follicular helper (Tfh) cells.
Th1 Cells
Th1 cells are involved in cell-mediated immunity and defense against intracellular pathogens such as viruses and certain bacteria. They secrete cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2). Th1 cells activate macrophages, enhance cytotoxic T cell responses, and promote the production of antibodies of the IgG2a isotype.
Th2 Cells
Th2 cells are crucial for humoral immunity and protection against extracellular parasites, such as helminths. They secrete cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13). Th2 cells stimulate B cell proliferation, antibody class switching to IgE and IgG1, and eosinophil activation.
Th9 Cells
Th9 cells are a subset of Th cells that specialize in producing interleukin-9 (IL-9). They are associated with allergic responses and immune regulation. Th9 cells can enhance allergic inflammation by promoting mast cell activation, eosinophil recruitment, and IgE production. Additionally, they may also play a role in anti-tumor immune responses.
Th17 Cells
Th17 cells are involved in immune responses against extracellular bacteria and fungi. They produce cytokines such as interleukin-17 (IL-17), interleukin-21 (IL-21), and interleukin-22 (IL-22). Th17 cells recruit neutrophils to the site of infection and contribute to tissue inflammation and barrier defense. Dysregulation of Th17 cells has been associated with autoimmune diseases.
Th22 Cells
Th22 cells are a recently discovered subset of Th cells that primarily produce interleukin-22 (IL-22). They are involved in skin immunity and have been implicated in various inflammatory skin conditions, such as psoriasis and atopic dermatitis. Th22 cells contribute to tissue repair and barrier function in the skin.
T Follicular Helper (Tfh) Cells
Tfh cells are specialized Th cells that are primarily involved in supporting B cell responses within germinal centers of lymphoid tissues. They express the chemokine receptor CXCR5 and provide critical help to B cells for antibody production and affinity maturation. Tfh cells secrete interleukin-21 (IL-21) and express the transcription factor Bcl-6, which are crucial for their function.
The differentiation and functional polarization of Th cells are driven by various factors, including cytokines, antigen presentation, co-stimulatory signals, and transcription factors. The balance and interplay between different Th cell subsets are critical for maintaining immune equilibrium and effective immune responses.
Understanding the functions and regulation of Th cells is crucial for unraveling the pathogenesis of various diseases, including infectious diseases, autoimmune disorders, allergies, and cancer. Dysregulation or imbalance in Th cell responses can lead to immune dysfunction and contribute to the development of immune-related diseases.
Th cells have become attractive targets for therapeutic interventions. Modulating Th cell responses through targeted immunomodulatory approaches holds promise for developing novel treatments for a wide range of diseases. Furthermore, Th cell-related research continues to provide insights into the complexities of the immune system, paving the way for advances in personalized medicine and immunotherapy.
Fig.1 Inter-conversion among T helper (Th) cell subsets. (Sun L, et al., 2023)
Importance and Regulatory Mechanisms of Th Cells in the Immune System
Th cells, or CD4+ T cells, play a crucial role in the immune system by coordinating and regulating immune responses. They are involved in both the adaptive and innate immune responses and contribute to various aspects of immune function. Here are the importance and regulatory mechanisms of helper T cells in the immune system:
- Antigen Recognition and Activation
Helper T cells recognize antigens presented by antigen-presenting cells (APCs) through their T cell receptors (TCRs). This recognition initiates a series of signaling events that lead to the activation of helper T cells. Upon activation, helper T cells undergo clonal expansion, producing a large number of effector cells to combat the specific antigen.
- Cytokine Production
Helper T cells are the primary producers of cytokines, which are small signaling molecules that regulate immune responses. Different subsets of helper T cells produce specific cytokines that direct immune responses. For example, Th1 cells produce interferon-gamma (IFN-γ) to enhance cellular immunity against intracellular pathogens, while Th2 cells produce interleukins such as IL-4, IL-5, and IL-13 to promote humoral immunity and defense against extracellular parasites.
- Activation of B Cells
Helper T cells provide essential signals to activate B cells, leading to antibody production. Through cell-cell interactions and the secretion of cytokines, helper T cells stimulate B cells to undergo class switching, affinity maturation, and antibody production. This collaboration between helper T cells and B cells is critical for the generation of effective antibody responses.
- Activation of Cytotoxic T Cells
Helper T cells play a role in the activation of cytotoxic T cells (CD8+ T cells). They provide signals that enhance the activation, proliferation, and effector functions of cytotoxic T cells, enabling them to recognize and eliminate infected or abnormal cells more efficiently.
- Regulation of Immune Responses
Helper T cells also have regulatory functions to maintain immune homeostasis and prevent excessive immune responses. Regulatory T cells (Tregs), a subset of helper T cells, suppress the activity of other immune cells, dampening immune responses and preventing autoimmunity. Tregs produce immunosuppressive cytokines like interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) to inhibit immune activation.
- Plasticity and Differentiation
Helper T cells exhibit plasticity and can differentiate into different subsets based on the microenvironment and specific signals. Through the expression of specific transcription factors and cytokines, helper T cells can switch between subsets, adapting their responses to different pathogens and immune challenges.
- Immune Memory
Helper T cells play a critical role in the establishment of immunological memory. Upon encountering an antigen, helper T cells undergo clonal expansion and generate long-lived memory cells. These memory cells can mount a more rapid and robust immune response upon re-exposure to the same antigen, providing enhanced protection against recurrent infections.
The regulatory mechanisms of helper T cells involve a complex interplay of antigen recognition, cytokine signaling, cell-cell interactions, and the expression of specific transcription factors. These mechanisms ensure precise coordination and modulation of immune responses, allowing the immune system to mount effective defenses against pathogens while maintaining tolerance to self-antigens. Understanding the importance and regulatory mechanisms of helper T cells is crucial for developing therapeutic strategies to modulate immune responses in various diseases and conditions.
Fig.2 CD4+ T helper subsets and their functions in the antitumoral immune response. (Andreu-Sanz D, et al., 2023)
Role and Research Progress of Th Cells in Various Diseases
Th cells play a significant role in various diseases by regulating immune responses and influencing disease outcomes. Research on Th cells in different diseases has provided valuable insights into their contributions and potential therapeutic interventions. Here is an overview of the role and research progress of Th cells in various diseases:
Autoimmune Diseases
Th cells are implicated in the development of autoimmune diseases, where the immune system mistakenly attacks self-tissues. For example:
- In multiple sclerosis (MS), Th1 and Th17 cells contribute to the inflammation and demyelination of nerve cells.
- Rheumatoid arthritis (RA) involves Th1 and Th17 responses, leading to chronic joint inflammation.
- In type 1 diabetes (T1D), Th1 cells target and destroy pancreatic beta cells.
Research has focused on understanding the mechanisms underlying Th cell dysregulation, such as aberrant cytokine production, defective regulatory T cells, and genetic susceptibility. Targeting Th cell subsets or modulating their cytokine profiles are potential therapeutic strategies.
Infectious Diseases
Th cells play a critical role in coordinating immune responses against pathogens. Research has focused on understanding their roles in various infectious diseases, including:
- HIV/AIDS: Th cells are preferentially targeted by the human immunodeficiency virus (HIV), leading to immune dysfunction and disease progression. Strategies to enhance Th cell responses and restore immune function are actively pursued.
- Tuberculosis (TB): Th1 cells producing IFN-γ are crucial for controlling Mycobacterium tuberculosis infection. The research aims to understand factors influencing Th1 responses and develop vaccines enhancing Th1 immunity.
- Malaria: Th1 and Th2 responses influence disease outcomes. Studies have explored the balance between pro-inflammatory and anti-inflammatory responses to optimize vaccine development and treatment strategies.
Allergic and Asthmatic Diseases
Th2 cells play a key role in allergic diseases, such as allergic rhinitis, asthma, and atopic dermatitis. Research has focused on understanding Th2 cell differentiation, cytokine regulation, and interactions with other immune cells. Targeting Th2 responses and developing immunotherapies to modulate Th cell function are areas of active investigation.
Cancer
Th cells have emerged as critical players in anti-tumor immune responses. Research has uncovered their roles in promoting tumor-specific cytotoxic T cell responses and orchestrating immune surveillance. Strategies to enhance Th cell responses, overcome tumor immune evasion, and develop Th cell-based immunotherapies, such as adoptive cell transfer, are being explored.
Neurological Disorders
Emerging evidence suggests the involvement of Th cells in neurological disorders, including neurodegenerative diseases and neuropsychiatric conditions. Th cells contribute to neuroinflammation and influence disease progression. Research aims to decipher the mechanisms of Th cell involvement and explore potential therapeutic interventions.
Research progress in understanding Th cells' roles in various diseases has led to the development of targeted therapies and immunomodulatory approaches. Strategies include cytokine blockade, antibody-based therapies, immune checkpoint inhibitors, and adoptive cell therapies. Personalized medicine approaches, considering individual Th cell profiles, hold promise for optimizing disease management and treatment outcomes.
It is important to note that the role of Th cells in different diseases is complex and can vary depending on the disease context and individual variations. Ongoing research continues to unravel the intricacies of Th cell biology and its implications for disease pathogenesis and therapeutic interventions.
Fig.3 Intratumoral balance of anti- vs pro-tumorigenic CD4+ TH cells determine immune response outcome. (Basu A,, et al., 2021)
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Related References
- Wan YY. Multi-tasking of Helper T Cells. Immunology. 2010;130(2):166-171.
- Sun L, Su Y, Jiao A, Wang X, Zhang B. T Cells in Health and Disease. Signal Transduct Target Ther. 2023;8(1):235.
- Andreu-Sanz D, Kobold S. Role and Potential of Different T Helper Cell Subsets in Adoptive Cell Therapy. Cancers. 2023; 15(6):1650.
- Basu A, Ramamoorthi G, Albert G, et al. Differentiation and Regulation of TH Cells: A Balancing Act for Cancer Immunotherapy. Front Immunol. 2021;12:669474.
