2025.07.07
Within the immune system, CD4+ T cells (helper T cells) play a critical role. They differentiate into distinct subsets, including Th1, Th2, and Th17 cells, each characterized by unique surface markers, cytokine secretion profiles, and specialized functions in immune responses. The balance among these T cell subsets is essential for maintaining immune homeostasis, while their dysregulation is linked to various inflammatory diseases, autoimmune disorders, and allergic reactions.
Th1 cells primarily mediate cell-mediated immune responses, with T-bet as their signature transcription factor. They typically express chemokine receptors such as CXCR3 and CCR5, which guide their migration to inflamed sites.
Key cytokines secreted by Th1 cells include:
• IL-2: A key growth factor promoting T cell proliferation and survival.
• TNF-α (tumor necrosis factor-α): A pro-inflammatory cytokine that activates macrophages and induces systemic responses like fever.
• IFN-γ (interferon-γ): The signature cytokine of Th1 cells, which activates macrophages to enhance their ability to kill intracellular pathogens.
Th1 cells target intracellular pathogens, such as viruses and certain bacteria (e.g., Mycobacterium tuberculosis). IFN-γ activates macrophages to boost phagocytosis and antigen presentation efficiency. However, excessive Th1 responses may cause tissue damage, associating with autoimmune diseases like rheumatoid arthritis and multiple sclerosis.
Th2 cells represent another major subset of helper T cells, with GATA3 as their signature transcription factor. They typically express chemokine receptors including CCR3, CCR4, and CRTH2.
Major cytokines secreted by Th2 cells include:
• IL-4: A key inducer of Th2 differentiation and a regulator of B cell class switching to IgE.
• IL-5: Critical for eosinophil activation and survival.
• IL-6: A multifunctional cytokine involved in acute-phase responses and B cell differentiation.
• IL-10: An important anti-inflammatory cytokine that suppresses Th1 responses and macrophage activation.
Th2 cells primarily drive immune responses against extracellular parasites (e.g., helminths) and allergens. Excessive Th2 activation is observed in allergic diseases such as asthma and atopic dermatitis. IL-4 and IL-13 promote B cell production of IgE, while IL-5 recruits and activates eosinophils, collectively contributing to anti-parasitic immunity and allergic reactions. Notably, IL-10, as a key anti-inflammatory factor, helps maintain immune balance by curbing excessive inflammation.
Th17 cells are a relatively newly discovered T cell subset, with RORγt as their signature transcription factor. They typically express CCR6, CD161, and the IL-23 receptor.
Signature cytokines secreted by Th17 cells include:
• IL-17A: The hallmark cytokine of Th17 cells, inducing various cells to produce inflammatory mediators.
• IL-17F: A cytokine functionally similar to IL-17A.
• IL-21: Involved in Th17 self-amplification and B cell regulation.
• IL-22: Contributes to the maintenance and repair of epithelial barriers.
Th17 cells play a key role in defending against extracellular bacterial and fungal infections, particularly at mucosal surfaces. IL-17 stimulates epithelial cells and fibroblasts to produce antimicrobial peptides, chemokines, and cytokines, recruiting neutrophils to infection sites. However, abnormal Th17 activation is associated with autoimmune diseases such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Studies show that IL-17A produced by Th17 cells is closely linked to skin inflammation and excessive keratinocyte proliferation in psoriasis models.
These three T cell subsets do not function independently but form a complex regulatory network. Th1 and Th2 cells exhibit mutual inhibition—IFN-γ suppresses Th2 differentiation, while IL-4 inhibits Th1 differentiation. Similarly, Th17 cells are regulated by other subsets: IFN-γ and IL-4 both suppress Th17 differentiation.
In disease states, this balance is often disrupted:
• Autoimmune diseases: Often involve excessive Th1 and/or Th17 responses with impaired regulatory T cell function.
• Allergic diseases: Characterized by excessive Th2 responses.
• Chronic infections: May feature insufficient Th1 responses or excessive Th2 activation.
Some therapeutic strategies aim to restore this balance. For example, regulating Th1/Th2 and Th17/Treg balance can alleviate intestinal inflammation in inflammatory bowel disease. Certain herbal components have been shown to “restore Th2/Th1 and Tregs/Th17 immune balance, primarily by inhibiting increases in the Th2/Th1 ratio and the production of their transcription factors (GATA3 and T-bet).”
Among the numerous cytokines secreted by Th1, Th2, and Th17 cells, several are particularly critical:
• IL-2: Primarily produced by Th1 cells, it is essential for T cell growth and survival, promoting clonal expansion through autocrine and paracrine mechanisms during early T cell activation.
• TNF-α: A major pro-inflammatory factor from Th1 cells, it aids in resisting intracellular pathogens but may cause tissue damage when overproduced. Elevated TNF-α levels correlate with disease severity in conditions like sepsis.
• IFN-γ: The signature Th1 cytokine, it is vital for macrophage activation, enhanced antigen presentation, and antiviral defense. Studies show increased IFN-γ levels in the cerebrospinal fluid of tick-borne encephalitis patients.
• IL-4: A key Th2 cytokine driving Th2 differentiation and IgE class switching. Elevated IL-4 levels correlate with disease severity in allergic reactions.
• IL-6: A multifunctional cytokine produced by Th2 cells and involved in Th17 differentiation. It, together with TGF-β, induces naïve T cells to differentiate into Th17 cells.
• IL-10: A critical anti-inflammatory cytokine produced by Th2 cells and regulatory T cells, it suppresses excessive immune responses. Research indicates that “IL-10 is negatively correlated with Th1 cytokines IL-2 and TNF-α, and positively correlated with Th2 cytokines IL-4 and IL-6.”
• IL-17A: The hallmark Th17 cytokine, it plays a pivotal role in mucosal defense and autoimmunity. In psoriasis models, increased IL-17A levels correlate with disease activity.
Understanding the biological properties of Th1, Th2, and Th17 cells has provided new insights into treating various diseases. In autoimmune disorders, monoclonal antibodies targeting Th17 cells or IL-17A (e.g., secukinumab) have been successfully used for psoriasis and ankylosing spondylitis. For allergic diseases, antibodies against Th2 cytokines (IL-4, IL-5, or IL-13) have shown promising efficacy.
Modulating the balance between T cell subsets has also emerged as a therapeutic strategy. For example, low-molecular-weight heparin (LMWH) “inhibits Th1 cytokine expression and enhances Th2 cytokine expression” in patients with recurrent miscarriage, improving pregnancy outcomes. Similarly, restoring “Th2/Th1 and Tregs/Th17 immune balance” alleviates intestinal inflammation in inflammatory bowel disease.
Advances in technologies like single-cell transcriptomics are deepening our understanding of T cell subsets. Recent studies reveal “high expression similarity between Th1 and Th17 phenotypes, while Th2 exhibits a distinct expression profile,” suggesting that traditional Th cell classification may require refinement. In the future, more precise T cell typing and personalized immunomodulatory strategies will bring new hopes for treating diverse diseases.
Conclusion
Th1, Th2, and Th17 cells, as major effector subsets of CD4+ T cells, play irreplaceable roles in immune defense, regulation, and pathological processes through their unique surface markers and cytokine profiles. A deeper understanding of their characteristics and interactions not only clarifies the pathogenesis of various diseases but also provides critical targets for immunomodulatory therapies.
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