T Helper Cells and Th2-Mediated IgE Class Switching
What Are T Helper (Th) Cells?
T helper cells are CD4+ lymphocytes that differentiate into distinct subsets with specialized functions, with Th2 cells being the primary orchestrators of IgE-mediated allergic responses through their production of IL-4, IL-5, and IL-13. 1
- Th1 cells produce IL-2, IFN-γ, and TNF-β, mediating delayed-type hypersensitivity reactions and cellular immunity against intracellular pathogens 2
- Th2 cells secrete IL-4, IL-5, IL-13, IL-6, and IL-9, providing optimal help for B-cell antibody production, particularly IgE class switching 2, 1
- Th0 cells represent an intermediate subset producing both Th1 and Th2 cytokines 2
- Both Th1 and Th2 cells produce IL-3, IL-6, GM-CSF, and TNF-α 2
Mechanism of Th2-Induced IgE Class Switching
IL-4 and IL-13 secreted by Th2 cells are primarily responsible for isotype class switching of B cells to produce IgE antibodies, with IL-4 being the critical initiating factor. 1
The IL-4 Pathway
- IL-4 serves as the major differentiation factor driving naive T cell differentiation toward the Th2 subtype, creating a self-amplifying loop 1
- IL-4 directly signals B cells to undergo class switch recombination from IgM/IgG to IgE production 3, 4
- T follicular helper (Tfh) cells, not Th2 cells, are the main controllers of IgE and IgG1 antibody responses through IL-4 secretion in germinal centers 3
- IL-4 production is regulated through two distinct pathways: GATA-3-mediated Il4-HS2 enhancer (Th2 cells) and Notch-mediated Il4-CNS-2 enhancer (Tfh cells) 3
The IL-13 Contribution
- IL-13 shares receptor components and signaling pathways with IL-4, providing overlapping functions in IgE synthesis 1
- Both IL-4 and IL-13 are deeply involved in eosinophil activation, mucus secretion, and airways remodeling beyond just IgE production 1
The Th1/Th2 Balance
- IFN-γ from Th1 cells inhibits IL-4-induced IgE synthesis, making the Th2/Th1 ratio critical for regulating IgE levels 4
- Reduced microbial exposure in early life shifts the immune balance toward pre-allergic Th2 responses 5
- Most allergen-specific human CD4+ T-cell clones exhibit a Th2 phenotype, while bacterial antigen-specific clones show Th1 profiles 2
Clinical Significance of Exaggerated Th2 Responses
Allergen-specific Th2 cells are selectively enriched in tissues affected by allergic inflammation and drive the complete allergic cascade through multiple mechanisms. 2
- IL-4 induces IgE production by B cells, which binds to mast cells and basophils, priming them for immediate hypersensitivity reactions 1, 6
- IL-5 promotes eosinophil proliferation, differentiation, and activation, contributing to tissue inflammation 1, 6, 2
- IL-13 drives epithelial barrier activation, mucous secretion, and metaplasia in asthma and allergic rhinitis 6
- IL-4 and IL-3 act synergistically as mast cell growth factors 2
- Th2 cells induce production of type 2-associated chemokines including TARC and eotaxin, recruiting more inflammatory cells 1
Common Pitfall to Avoid
The traditional view that Th2 cells are the primary source of IL-4 for IgE class switching is incomplete. Recent evidence demonstrates that Tfh cells in germinal centers, not peripheral Th2 cells, are the main controllers of IgE antibody responses 3. However, Th2 cells remain critical for tissue inflammation and amplification of allergic responses through their cytokine production at sites of allergen exposure 2.
Therapeutic Implications
- Anti-IL-4/IL-13 receptor antibodies (dupilumab) successfully treat severe chronic rhinosinusitis with nasal polyps and asthma by blocking both IL-4 and IL-13 signaling 1
- Anti-IL-5 antibodies (mepolizumab, reslizumab) reduce eosinophilic inflammation in appropriately selected patients 1, 6
- These targeted therapies validate the central role of Th2 cytokines in allergic disease pathophysiology 6