1 Conceptual Framework
Immunity is organized into two inter-locking layers that share evolutionary continuity yet exhibit distinct kinetics, receptor usage and memory capacity.
- Innate immunity delivers rapid, stereotyped responses through germline-encoded sensors and effector modules.
- Adaptive immunity evolves clonally distributed antigen receptors, enabling high-affinity, pathogen-tailored responses and long-lived immunological memory.Integration of these arms is continuous: innate cues license and shape adaptive responses, while adaptive effectors feed back to remodel innate circuits.
2 Innate Immunity
| Theme | Details | Selected mechanistic highlights |
|---|---|---|
| 2.1 Cellular sentinels | Tissue-resident macrophages, dendritic cells (DCs), γδ T cells, innate lymphoid cells (ILCs) and epithelia form a layered surveillance network. Ontogeny ranges from yolk-sac–derived, self-maintaining macrophages to bone-marrow–derived monocytes recruited on demand (emergency myelopoiesis). | Stress-induced granulocyte–monocyte progenitor (GMP) skewing is orchestrated by IL-6/STAT3 and NR4A1 signalling, balancing neutrophil output versus stem-cell exhaustion. |
| 2.2 Pattern recognition | Germline-encoded PRRs (TLRs, CLRs, RLRs, NLRs, cGAS, AIM2-like receptors) detect PAMPs and DAMPs. DAMP sensing extends beyond intracellular alarmins to inter-organ signals, forming a trans-tissue danger circuitry. | Inflammasome activation (e.g., NLRP3) integrates ion flux, mitochondrial ROS and cardiolipin exposure to gate IL-1β/IL-18 release and pyroptosis. |
| 2.3 Soluble mediators | Complement provides opsonization (C3b), membrane-attack complex formation (C5b-9) and anaphylatoxin signalling (C3a/C5a). Beyond serum, intracellular “complosome” C3 fragments tune metabolic checkpoints (mTOR) and epigenetics. | Dysregulated C5aR1–PI3Kγ signalling sustains myeloid-derived suppressor cell (MDSC) expansion in cancer microenvironments. |
| 2.4 Effector modules | Phagocytosis couples to inducible antibacterial programs: LC3-associated phagocytosis, guanylate-binding protein pore formation, metal intoxication, lipid-mediated control and nitric-oxide synthase activity. | Interferon-γ licences macrophage mitochondrial re-wiring, boosting itaconate-dependent inhibition of bacterial isocitrate lyase. |
| 2.5 Innate memory (“trained immunity”) | β-glucan, BCG or oxidized LDL provoke long-lived H3K4me3/H3K27ac marks in myeloid progenitors, enhancing future cytokine production or, conversely, inducing tolerance via H3K9me2. Effects persist for months in humans and influence vaccine responsiveness. | Metabolic control is mTOR-HIF-1α–driven, shifting glycolysis–OXPHOS balance and fuelling acetyl-CoA for histone acetylation. |
3 Adaptive Immunity
3.1 Antigen-receptor generation
Somatic V(D)J recombination (RAG1/2), junctional diversity (TdT) and somatic hyper-mutation together create >10¹³ potential immunoglobulin/TCR specificities. Allelic exclusion ensures monospecificity.
3.2 Antigen presentation & selection
- MHC-I displays cytosolic peptides to CD8⁺ T cells; immunoproteasomes and TAP transport optimize epitope yield.
- MHC-II presents vesicular peptides to CD4⁺ T cells; DM/DO editing shapes peptide–MHC stability.
- Central tolerance deletes or reprograms self-reactive clones; AIRE/FEZF2-driven ectopic antigen expression in medullary thymic epithelial cells is critical.
3.3 Effector T-cell subsets
Th1, Th2, Th17, Tfh, Treg and Trm lineages arise from STAT-guided transcriptional hubs (e.g., TBET, GATA-3, RORγt). Cytolytic armament includes perforin, granzyme, Fas-L, and cytokines (IFN-γ, TNF-α).
3.4 B-cell differentiation
CD40-CD40L interactions and Tfh-derived IL-21 drive germinal-centre reactions: class-switch recombination via AID, affinity maturation and selection of high-affinity clones. Long-lived plasma cells (LLPCs) persist in CXCL12⁺ niches.
3.5 Immunological memory
Memory T and B cells display metabolic fitness (mitochondrial fusion, fatty-acid oxidation) and chromatin “poising.” Tissue-resident memory (T_RM) cells express CD69/CD103, providing rapid barrier defence.
4 Crosstalk, Regulation & Tolerance
- Patterning innate instruction of adaptive immunity — DC subset, cytokine milieu, and costimulatory ligands tailor T-cell polarization; C3d–CR2 lowering B-cell activation threshold exemplifies complement bridging.
- Danger versus self — The Matzinger danger model reframes immune activation as a response to perturbation, integrating PAMP and DAMP cues; central to vaccine adjuvant design and sterile-inflammation therapeutics.
- Sterile inflammation — Mitochondrial DNA or HMGB1 released during trauma or necroptosis activates TLR9/TLR4, perpetuating auto-inflammation (e.g., gout, SLE).
5 Clinical & Translational Perspectives
| Frontier | Illustrative applications |
|---|---|
| Innate modulation | Trained-immunity–based boosters (e.g., BCG-derived MTBVAC) enhance heterologous viral protection; C3 inhibitors (pegcetacoplan) expand beyond PNH to dry AMD. |
| Adaptive-targeted therapy | CAR-T cells redirected to auto-reactive B cells achieve remission in SLE; PD-1/IL-21 axis tuning augments checkpoint efficacy. |
| Integrated biomarkers | Emergency myelopoiesis signatures (G-CSF, neutrophil-to-lymphocyte ratio) predict sepsis outcomes; memory-subset imprinting guides vaccine schedules in aging populations. |
6 References
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- Lam, N., Lee, Y., & Farber, D. L. (2024). A guide to adaptive immune memory. Nature Reviews Immunology, 24, 810–829. https://doi.org/10.1038/s41577-024-01040-6
- Mastellos, D. C., Hajishengallis, G., & Lambris, J. D. (2024). A guide to complement biology, pathology and therapeutic opportunity. Nature Reviews Immunology, 24, 118–141. https://doi.org/10.1038/s41577-023-00926-1
- Matzinger, P. (1994). Tolerance, danger, and the extended family. Annual Review of Immunology, 12, 991–1045. https://doi.org/10.1146/annurev.iy.12.040194.005015
- Murphy, K., & Weaver, C. (2022). Janeway’s immunobiology (10th ed.). W. W. Norton.
- Sweet, M. J., Ramnath, D., & Kapetanovic, R. (2024). Inducible antibacterial responses in macrophages. Nature Reviews Immunology, 25, 92–107. https://doi.org/10.1038/s41577-024-01080-y
- Swann, J. W., Olson, O. C., & Passegué, E. (2024). Made to order: Emergency myelopoiesis and demand-adapted innate immune cell production. Nature Reviews Immunology, 24, 596–613. https://doi.org/10.1038/s41577-024-00998-7
- Vuscan, P., Kischkel, B., Joosten, L. A. B., & Netea, M. G. (2024). Trained immunity: General and emerging concepts. Immunological Reviews, 323, 164–185. https://doi.org/10.1111/imr.13326