Understanding the Roles of TH1, TH2, and TH17 Cells in Immune Responses - A Deeper Dive.
In this month’s blog we are considering T-helper (TH) cells. Among the diverse types of TH cells, the three main subsets - TH1, TH2, and TH17 - play distinct yet complementary roles in immune defence, each focusing on different aspects of pathogen clearance and inflammation.
T-helper (TH) cells are then a crucial subset of immune cells that help coordinate the body’s defence against infections and manage autoimmune responses. They are a type of CD4+ T cell, meaning they express the CD4 protein on their surface, which helps them interact with other immune cells. They particularly assist in regulating and amplifying the immune response by releasing specific cytokines that direct the behaviour of other immune cells based on the type of pathogen encountered.
The TH1 subtype – The Defenders Against Intracellular Pathogens
TH1 cells are primarily involved in the defence against intracellular pathogens, such as viruses, some intracellular bacteria and protozoa. Their main function is to promote a cell-mediated immune response, meaning they help activate cytotoxic T lymphocytes (CTLs) and macrophages to eliminate infections hiding inside host cells.
TH1 polarisation
The journey of TH1 polarisation begins when naïve CD4+ T cells encounter an antigen presented by antigen-presenting cells (APCs), such as dendritic cells, macrophages, or B cells. These APCs express antigen fragments on their surface bound to major histocompatibility complex (MHC) class II molecules. The interaction between the T-cell receptor (TCR) on the naïve T cell and the peptide-MHC II complex on the APC initiates the first signal required for T cell activation. The key to TH1 differentiation lies in the cytokine milieu around the naïve T cell during activation. For TH1 polarisation to occur, specific cytokines must be present in the surrounding environment the most important being interleukin-12 (IL-12), which is produced primarily by dendritic cells and macrophages in response to infection by intracellular pathogens. This promotes STAT4 (Signal Transducer and Activator of Transcription 4) signalling and the transcription factor T-bet production in the naïve T-cell – T-bet being the master regulator of TH1 differentiation. IL-18 works with IL-12 to enhance T-bet and IFN-γ expression during TH1 differentiation. During TH1 polarisation, there is often a suppression of other T helper subsets.
TH1 and cytokine production.
Once polarised into TH1 cells, they begin to secrete a distinct set of cytokines that drive a robust immune response, geared toward eliminating infected cells and pathogens. TH1 cells are most often defined by their production of IL-2 and IFN-γ but have been reported to produce a number of cytokines including TNF-α and TNF-β lymphotoxin, and granulocyte-macrophage colony-stimulating factor which activate macrophages, CTLs, and other immune cells to clear infections. IFN-y is the hallmark cytokine of TH1 cells and is the main effector molecule that characterises the TH1 response. IFN-γ is a potent activator of macrophages, enhancing their ability to kill engulfed pathogens through the production of reactive oxygen species and nitric oxide. IFN-γ also upregulates the expression of MHC class I and II molecules on APCs, improving their ability to present antigens to T cells and enhance the immune response. Finally, IFN-γ stimulates the differentiation of naïve CD8+ T cells into CTLs, which can directly kill infected or cancerous cells. While promoting inflammation necessary for pathogen clearance, IFN-γ also regulates other cytokine profiles, thus maintaining a balance between immune activation and tolerance.
TH1 and autoimmunity
TH1 responses are crucial for immunity but dysregulation of TH1 activity is closely linked to the development of autoimmune diseases. Autoimmune diseases occur when the immune system, which is typically adept at distinguishing between "self" and "non- self," starts targeting healthy cells. An overactive or misdirected TH1 response can lead to tissue damage and chronic inflammation, hallmark features of autoimmune diseases. The key to TH1-driven autoimmunity lies in the cytokines these cells release, particularly IFN-γ and TNF-α. These cytokines promote inflammation and recruit other immune cells to sites of infection, but when produced inappropriately or disproportionately, they can disrupt the balance between immune activation and tolerance leading to excessive damage of own tissues. Multiple sclerosis, Diabetes type 1 and Crohn’s disease for example involve TH1dysregulation.
The TH2 Subtype – The Defenders against extra cellular pathogens
TH2 cells mainly respond to extracellular pathogens, such as helminths (parasitic worms), certain bacteria, allergens and toxins. Their main role is to stimulate humoral immunity, which involves antibody production by B cells and the activation of other immune mechanisms to fight infections that reside outside cells.
TH2 Polarisation
As with TH1 polarisation, naïve CD4+ T cells are activated by APCs which process and present antigens (from pathogens, allergens, etc.) in the context of MHC class II molecules, which are recognised by TCR on the naïve T cells. For TH2 differentiation to occur, the presence of a different set of specific cytokines is required. The most important of these is interleukin-4 (IL-4), which is produced by mast cells, basophils, and other immune cells in response to allergens or parasitic infections. IL-4 is initiates TH2 differentiation by binding to the IL-4 receptor on naïve CD4+ T cells. This activatesthe STAT6 (Signal Transducer and Activator of Transcription 6) pathway, which plays a central role in inducing the transcription factor GATA3 - the master regulator of TH2 cell differentiation. GATA3 suppresses the expression of genes associated with other T helper subsets (such as TH1 and TH17), ensuring that the T cell commits to the TH2 lineage.
TH2 and cytokine production
IL-4, IL-5, IL-9 and IL13 are the main cytokines produced by TH2 cells. IL-4 is the hallmark cytokine and promotes IgE production by B cells, which is critical in defending against helminths. In the context of allergy, IL-4 contributes to the development of allergic reactions by causing the overproduction of IgE antibodies that bind to allergens and trigger mast cell degranulation (release of histamine and other mediators). IL-4 also helps in the recruitment and activation of other immune cells, such as eosinophils, which are key players in allergic inflammation and essential in fighting parasitic infections. IL-25 and IL-33 are other cytokines secreted by TH2 cells participating in the initiation and progression of the inflammatory response.
TH2 and autoimmunity
TH2 cytokines, particularly IL-4, play a critical role in B cell activation, promoting the production of autoantibodies. In diseases like systemic lupus erythematosus (SLE), autoantibodies target the body’s own tissues (such as DNA, histones, and ribonucleoproteins), leading to widespread tissue damage. IL-4 and other TH2 cytokines exacerbate this by enhancing B cell differentiation and antibody production, amplifying the autoimmune response. The cytokines released by TH2 cells also contribute to chronic inflammation and tissue remodelling in autoimmune diseases. Rheumatoid arthritis is another TH2 driven autoimmune disease.
The TH17 subtype - Defenders Against Fungi and Bacteria
TH17 cells are involved in defending against extracellular bacteria and fungi, especially at mucosal surfaces like the gut, skin, and lungs. These cells are also important in maintaining mucosal integrity and controlling inflammation. Unlike other T helper cells contribute to immune responses through mechanisms that involve inflammation and recruitment of neutrophils to the site of infection. When dysregulated, they are also implicated in a variety of autoimmune and inflammatory diseases.
TH17 polarisation
Like in the case of TH1 and TH2, polarisation of TH-17 starts when naïve T cells encounter APCs that present an antigen in the context of MHC class II molecules. The major driver of TH17 polarisation is IL-6, which is produced by various APCs in response to infection or inflammation. TGF-β is also important for initiating TH17 differentiation, but it alone is not enough. IL-21, produced by activated TH17 cells themselves, also reinforces the polarization process. IL-23 plays a critical role in stabilising TH17 cells once they have differentiated, promoting their survival and expansion. The transcription factor RORγt (retinoic acid-related orphan receptor gamma t) is the overall master regulator of TH17 differentiation. In the presence of IL-6, TGF-β, and IL-21, RORγt drives the expression of key TH17 cytokines. Additionally, STAT3 (Signal Transducer and Activator of Transcription 3) is activated by IL-6 and IL-21, helping to promote the expression of RORγt and other genes involved in TH17 differentiation. One of the unique features of TH17 cells is the autocrine feedback loop involving IL-21. Once differentiated, TH17 cells produce IL-21, which further stimulates their own growth and differentiation. This reinforces the TH17 response and contributes to the amplification of inflammation.
TH17 cytokines
The primary cytokine produced by TH17 cells is IL-17, which exists in several isoforms, including IL-17A and IL-17F. These cytokines, along with others like IL-22, play pivotal roles in immune responses and disease. IL-17A and IL-17F are crucial for the recruitment of neutrophils and monocytes to sites of infection or inflammation. They also induce the production of pro-inflammatory cytokines and chemokines in various tissues, leading to an amplification of the inflammatory response. IL-22 primarily acts on epithelial cells to enhance their barrier function and promote tissue repair. IL-21 supports the expansion and survival of TH17 cells and promotes B cell differentiation, further contributing to the immune response.
TH17 and autoimmune disease
The same inflammatory processes that make TH17 cells effective in combating infections can, when dysregulated, contribute to a variety of autoimmune conditions. For example, in Rheumatoid Arthritis, an autoimmune disease characterised by chronic inflammation of the joints, TH17 cells are implicated in joint destruction. IL-17 recruits neutrophils to the synovium (the tissue lining the joints), promoting the production of matrix-degrading enzymes that damage cartilage and bone. Multiple sclerosis, a neuroinflammatory disease, involves TH17 cells crossing the blood-brain barrier and inducing inflammation in the central nervous system. IL-17 promotes the activation of astrocytes and microglia, leading to myelin degradation and neuronal damage. In psoriasis, an autoimmune skin disorder, TH17 cells play a critical role in the abnormal proliferation of keratinocytes, the skin cells responsible for forming the outer layer of the epidermis. IL-17 and IL-22 induce epidermal hyperplasia and the formation of thick, scaly plaques on the skin.
In summary, the immune system relies heavily on the coordinated actions of TH1, TH2, TH17 to defend the body from infections, maintain homeostasis, and regulate inflammation. Each of these subsets plays a specialised role in immune protection andtolerance. However, the dysregulation of any one subset can lead to a variety of diseases, from autoimmune disorders to allergies, chronic inflammation, and even cancer. Understanding the roles and interactions of these immune cells is essential for developing targeted therapies that can modulate immune responses in a precise and effective manner.
T-Helper Cell Typing via Colab Services
T-helper cell typing refers to the process of assessing the relative proportions or activity levels of T-Helper cell subsets in a patient’s immune system. As discussed, many diseases, including autoimmune and allergic disorders, are associated with imbalances in TH1, TH2, and TH17 responses. T-helper cell typing can provide critical insights into which immune pathways are overactive or underactive in a particular individual. It can also be useful for tracking the course of an illness or efficacy of an intervention - changes in the balance of TH subsets may indicate disease progression or the effectiveness of ongoing treatment. For example, a shift from TH1 dominance to a more balanced TH1/TH2 ratio might suggest an improvement in an autoimmune disease or a response to an intervention such as micro-immunotherapy.
Our LM3539 Immune Helper Cell Typing (MeGeMIT) is part of the MeGeMIT series of tests relating to Micro-immunotherapy and includes the following markers: T4 T helper rel, T helper (1) cells, T helper (2) cells, Quotient TH1/TH2, T helper (17) cells, TH17 cells related, T-helper 1/T-helper 17 cells, T reg cells, Quotient Th17. Treg.
If the subject of Micro-immunotherapy (MIT) is of interest to you, please consider reviewing our blog from July 2024. We also offer micro-immunotherapy training and have a range of associated tests available. We have two upcoming sessions on micro- immunotherapy and our recent training is available via recording to better prepare you for any upcoming training.
Evening online Advanced Training 30th April 2025- Dr Meuschel will be delivering the 3rd in our current series of MIT training.
Full live day masterclass taking place on the 28th June in London as the culmination of our current series of MIT training- This masterclass will be focusing on Lymphocyte Typing Testing and Micro-immunotherapy Protocols. We still have a few places left. Please get in touch for more information.