Table 3.
Transcriptional and Signaling Networks Regulating Type 2 Immunity
| Pathway/Network | Key Molecules | Function | Regulatory Mechanism | References |
|---|---|---|---|---|
| IL-4/STAT6/GATA3 Axis | IL-4, IL-4R, CD44v5, STAT6, GATA3, TCF-1, SATB1, Grail, CIS, BLOC1S1, STING, NF-κB | Drives Th2 cell differentiation, initiates transcription of Th2 signature cytokines (IL-4, IL-5, IL-13), inhibits Th1 pathway | IL-4 binds IL-4R; CD44v5 stabilizes IL-4Rα. STAT6 phosphorylation induces GATA3 expression. GATA3 & STAT6 co-regulate Th2 genes. Inhibits suppressive TCF-1 isoforms; Induces SATB1. Negative Feedback: Grail degrades STAT6; CIS inhibits STAT6. BLOC1S1 loss -> mtDNA leakage -> STING-NF-κB activation -> STAT6 phosphorylation |
44-52 |
| STAT6-Independent Pathway (Notch) | Notch, Jagged2, KLF2, HIF-1α, Mib1, KLF2/S1PR1 axis | Acts as a "licensing" signal, promotes egress of Th2 cells from draining lymph nodes to effector tissues like the lung, independent of GATA3 | "Licensing" signal for Th2 cell egress from lymph nodes. GATA3-independent function. Migration achieved by upregulating KLF2/S1PR1 axis. Regulated by DC signals: KLF2 (via HIF-1α) negatively regulates Jagged2. Mib1 is a necessary molecular switch for ligand activity. |
53-55 |
| STAT6-Independent Pathway (IL-2/STAT5) | IL-2, STAT5, C-MAF, Eos, SOCS (CIS, SOCS2) | In human CD4+ T cells, IL-2 via STAT5 induces C-MAF expression, promoting Th2 differentiation; Eos enhances STAT5 activity | IL-2 activates STAT5, directly inducing C-MAF expression. Eos forms a complex with STAT5, enhancing its phosphorylation and activity. Negative Feedback: CIS and SOCS2 inhibit STAT5 and STAT6 phosphorylation. |
56-59 |
| GATA3 as Common Core Transcription Factor for Th2 and ILC2s | GATA3, Distal Enhancers (Gata3 +674/762, G3SE, mG900), IL-10, STAT3, Blimp-1, Bcl6, BACH2 | Drives the differentiation, maintenance, and function of Th2 cells and ILC2s; regulates expression of type 2 cytokines (e.g., IL-4, IL-5, IL-13) | Regulated by cell-specific enhancers (e.g., G3SE for ILC2s; mG900 for Th2). Regulated by cell-specific upstream TFs: IL-10-STAT3-Blimp-1-Bcl6 axis promotes GATA3 in lung Th2. BACH2: Positive regulator in ILC2s, inhibitory in Th2. GATA3 dosage affects cell plasticity (e.g., skin ILC2s). Expression is independent of auto-positive feedback. |
60-67 |
| Negative Regulatory Network of Type 2 Immunity | T-bet, Tregs, BACH2, miR-15/16, DOCK8, PGI₂, IL-37, TSLP, IL-6, SOCS3, sCTLA-4, BAFF | Maintains immune homeostasis, suppresses allergic inflammation; Tregs inhibit activation of Th2 cells and ILC2s | T-bet: Directly inhibits Th2 cell program. Tregs: Function maintained by intrinsic molecules (BACH2, miR-15/16, DOCK8). Treg External "Licensing": PGI₂ activates suppression function. IL-37 increases Treg numbers and IL-10. TSLP maintains Treg lineage stability. IL-6/SOCS3 Pathway: Inhibits IL-2 signaling needed for Th2. sCTLA-4: Suppresses type 1 immunity, permits type 2 immunity. BAFF: Inhibits Treg function, leading to allergy. |
68-74, 76, 77 |