Th2 cell

**Differentiation** - Naive CD4+ T cell + IL-4 (from mast cells, basophils, ILC2s, or an early T cell source) -> STAT6 activation -> GATA3 (master transcription factor) -> Th2 phenotype. - Th1 and Th2 cross-inhibit each other. IFN-γ (from Th1) inhibits Th2, and IL-4 and IL-10 inhibit Th1. - Epithelial alarmins (TSLP, IL-25, IL-33) promote Th2 and ILC2 responses at barrier surfaces.

**Key cytokines and effects** - **IL-4:** Drives B-cell class switching to IgE (and IgG4). It also promotes Th2 differentiation by positive feedback. - **IL-5:** Activates and recruits eosinophils and promotes IgA class switching. - **IL-13:** Increases mucus production by goblet cells, causes airway hyperreactivity, and increases smooth muscle contractility. It also promotes alternatively activated (M2) macrophages and fibrosis. - **IL-10:** Anti-inflammatory. It inhibits Th1 and macrophage activity.

**Physiologic role** - Defense against extracellular parasites (helminths). IgE-coated worms are attacked by eosinophils (ADCC via major basic protein), and mast cells degranulate. - Increased mucus secretion and gut motility help expel worms ("weep and sweep").

**Clinical significance** - **Type I hypersensitivity:** Th2 -> IgE -> mast cell sensitization -> degranulation on re-exposure (histamine, leukotrienes). - **Atopic diseases:** Allergic rhinitis, atopic dermatitis (eczema), allergic asthma, and food allergy. Eosinophilia is common. - **Asthma:** Th2-high (eosinophilic) phenotype is the classic type. - **Eosinophilic esophagitis:** Th2-driven. - **Hyper-IgE syndrome (Job syndrome):** Due to STAT3 mutation (AD), which impairs Th17 differentiation. It presents with FATCHEK features (coarse Facies, cold (non-inflamed) Abscesses, retained primary Teeth, Eczema, high IgE). Eosinophilia and recurrent staphylococcal infections are also seen. Know that it is a Th17 defect, not a Th2 defect. - **Leprosy:** The Th2 response (lepromatous form) is ineffective against intracellular M. leprae. Th1 (tuberculoid form) is protective.

**Targeted therapies (high-yield pharmacology)** - **Omalizumab:** Anti-IgE. - **Mepolizumab and reslizumab:** Anti-IL-5. Benralizumab: anti-IL-5Rα. - **Dupilumab:** Anti-IL-4Rα (blocks IL-4 and IL-13 signaling). Used in atopic dermatitis, asthma, and eosinophilic esophagitis. - **Corticosteroids** and **montelukast** (leukotriene receptor antagonist) also reduce Th2-mediated inflammation.

**Th1 vs Th2 quick comparison** - Th1: IL-12 and IFN-γ -> T-bet -> secretes IFN-γ -> activates macrophages, intracellular pathogens, type IV hypersensitivity. - Th2: IL-4 -> GATA3 -> secretes IL-4, IL-5, IL-13 -> eosinophils, IgE, helminths, allergy.

**Pearl:** Th2 cells are CD4+ and recognize antigen on MHC class II. T cell help to B cells also requires CD40L–CD40 interaction.