Category: immune_innate
Naive CD4+ T cells polarize into distinct effector lineages based on cytokine environment + master transcription factors. Lineage signatures: (1) Th1 — IL-12 + IFN-γ; T-bet (TBX21); cytokines IFN-γ + TNF-α + IL-2; intracellular pathogens + macrophage activation. (2) Th2 — IL-4; GATA3; cytokines IL-4 + IL-5 + IL-13; helminth defense + allergic disease (cross-link [[asthma_th2_eosinophil_inflammation]]). (3) Th17 — TGF-β + IL-6 + IL-23; RORγt; cytokines IL-17A/F + IL-22; extracellular bacteria + fungi at mucosa; autoimmune (psoriasis, IBD, axial spondylitis). (4) iTreg — TGF-β + IL-2; FoxP3; cytokines IL-10 + TGF-β; immune tolerance + suppressing other lineages. (5) Tfh — IL-6 + IL-21; Bcl-6; CXCR5; B-cell germinal center help. Plasticity: lineages are not fully terminal — Th17 ↔ iTreg interconversion (shared TGF-β requirement; IL-6 sets the balance); ex-Th17 → Th1-like in chronic inflammation. Metabolic profile: effector Th1/Th17 prefer glycolysis (mTORC1-dependent); Treg prefer fatty-acid oxidation (AMPK-dependent — cross-link [[ampk_signaling]] + [[mtor_signaling]]). Disease relevance: Th1 — MS, T1D; Th2 — asthma, allergy; Th17 — psoriasis, IBD, AS; Treg deficiency — IPEX (FoxP3 LOF). Therapeutic landscape: calcineurin inhibitors (block IL-2 → all lineages); mTOR inhibitors (rapamycin — expands Treg, suppresses Teff); methotrexate; JAK inhibitors (tofacitinib, baricitinib — IL-6/IFN/IL-12/23 downstream); cytokine-specific biologics: anti-IL-17 (secukinumab, ixekizumab), anti-IL-23 (ustekinumab, risankizumab); anti-IL-4Rα (dupilumab — Th2 blockade); CTLA-4-Ig (abatacept). Cross-links: [[kynurenine_tryptophan_pathway]] (IDO → Treg induction), [[asthma_th2_eosinophil_inflammation]], [[calcineurin_nfat_t_cell_activation]].