An Introduction to Developmental Immunology

By Deliana InfanteReviewed by Lily Ramsey, LLM

Developmental immunology is a fascinating field that explores the formation and maturation of the immune system from the embryonic stage through adulthood. It entails grasping the functions of both the innate and adaptive immune systems, as well as the development of hematopoietic stem cells.

Image Credit: YAKOBCHUK VIACHESLAV/Shutterstock.com

What is Developmental Immunology?

Developmental immunology is a field that studies how the immune system forms and matures during the growth of an organism.¹ It involves both the innate immune system, which provides immediate defense against infections, and the adaptive immune system, which develops a more specific response over time.¹

Throughout life, all blood cells in an organism originate from hematopoietic stem cells (HSCs).¹ Not only can they specialize toward all blood lineages, but they can also renew their own population to sustain long-term blood regeneration potential.¹

These cells undergo asymmetrical divisions in the bone marrow to produce one stem cell and one progenitor cell, ensuring the maintenance of the HSC pool while generating cells destined for differentiation, such as immune cells.¹ This process is crucial for sustaining blood cell production throughout life.¹

However, there are conditions of innate or acquired defects in the regulation of this process that can cause diseases like leukemia, lymphoma, myelodysplastic syndromes, or severe immunodeficiencies.^2-3

The study of HSCs and the bone marrow microenvironment has led to significant scientific and clinical advancements for the treatment of different conditions, such as STRIMVELIS for ADA-SCID⁴, ZYNTEGLO for transfusion-dependent β-thalassemia⁵, and LIBMELDY for metachromatic leukodystrophy⁶.

HSC research has led to the development of a variety of experimental models (e.g., iPSCs, aSCs, 3D organoids, organ-on-a-chip), enabling the study of the immune cell’s microenvironment in pathological conditions like cancer, autoimmune diseases, and tissue regeneration.^7-8

Foundational Concepts in Immune Cell Development

Hematopoietic cell formation is a complex process that starts early in embryonic development and produces all blood cells.⁹ In the third week of development, the human yolk sac is where hematopoiesis begins.⁹ This early stage is crucial as it marks the beginning of blood cell formation in the embryo.⁹

The yolk sac-derived stem cells are primarily limited to myelo-erythroid development, which includes the formation of red blood cells and certain types of white blood cells.⁹ Concurrently, in the splanchnopleura, the embryo develops the ability to make blood cells.⁹

Unlike yolk sac-derived stem cells, these embryonic hematopoietic stem cells (HSCs) have the potential for lymphopoiesis, which includes the formation of lymphocytes.⁹ From weeks 6 to 22 of pregnancy, the liver serves as the main location of hematopoiesis; following this, the bone marrow takes over as the main location of blood cell production.⁹

The subsequent development of the immune system gives rise to myeloid and lymphoid lineages.¹⁰ Myeloid cells include monocytes, macrophages, myeloid dendritic cells, granulocytes, and mast cells.¹⁰ These cells are part of the innate immune system and participate in the innate response against a pathogenic stimulus.¹⁰ 

Lymphoid cells include NK cells, and B and T cells, which act in innate and adaptive immunity, respectively.¹⁰ For adaptive immunity to yield a more specific immune response, B and T cells are indispensable.¹⁰ T lymphocytes undergo the final stages of development in the thymus, despite the fact that they are initially generated in the early embryo liver and the bone marrow.¹⁰

On the other hand, NK cells also belong to the lymphoid lineage but play a role in the innate response.¹⁰

Learn more about embryogenesis

Recent Advances in Developmental Immunology

Through the use of cutting-edge analytical methods, new immune cell subsets have been identified, and our understanding of the roles cytokines play in immune cell development and behavior has deepened.¹¹

Single-cell RNA sequencing (scRNA-seq) has been instrumental in identifying rare immune cell populations that are often overlooked in bulk analyses due to their low abundance.¹¹

A noteworthy study mapped the effects of 86 cytokines on 17 immune cell types, creating a comprehensive "dictionary of immune responses" that enhances understanding of cytokine roles in health and disease.¹¹

The use of multi-omic strategies for single-cell sequencing has enabled the simultaneous profiling of the genome, transcriptome, and epigenome within the same cell, offering deeper insights into the regulatory mechanisms of immune cell development.¹²

The data from these technologies is used to inform multiparameter flow cytometry and cell sorting experiments, ensuring functional relevance.¹² These integrative approaches have led to the discovery of various immune populations, including regulatory B cells¹³ and rare Th17 cell subsets^12,14, which play a crucial role in both health and disease.

Furthermore, single-cell transcriptomics and flow cytometry have revealed significant changes in immune cell composition during tumor progression in models like glioblastoma.¹⁵

These sequencing technologies facilitate the study of the molecular mechanisms of immune cell recruitment to the tumor microenvironment and the identification of gene expression patterns at different disease stages.¹⁵

Clinical and Practical Applications

The development of recombinant monoclonal antibodies is a direct result of understanding how the immune system develops and functions.¹⁶ These antibodies can be designed to target specific antigens found on cancer cells or to modulate the immune system in autoimmune diseases.¹⁶

Examples include drugs like rituximab for rheumatoid arthritis¹⁷ and various B-cell lymphomas¹⁸, and trastuzumab for HER2-positive breast cancer.¹⁹

Knowledge of immune cell development has also been instrumental in the creation of therapies like hematopoietic stem cell transplantation (HSCT)²⁰ and chimeric antigen receptor T-cell (CAR-T) therapy.¹⁶

HSCT can be used to reset the immune system in autoimmune diseases like multiple sclerosis. At the same time, CAR-T cell therapy has revolutionized the treatment of certain types of cancer by engineering a patient's T cells to attack cancer cells.^16,20

More from AZoLifeSciences: Are CAR-T Cells the Future of Infectious Diseases Treatment?

Future Directions

These therapies are being expanded to other areas, including fibrosis and metabolic diseases, underscoring their extensive potential for clinical applications.²⁰

Many of these therapies were initially developed for cancer; in 2024, they are being adapted for infectious diseases.²¹ This is because these therapies aim to regulate signaling pathways involved in the metabolic and immunologic functions of the tumor microenvironment, which are also relevant in infectious diseases.²¹

The insights gained from developmental immunology also enhance vaccine strategies.²¹ By understanding how infections induce immune suppressor cells, researchers are exploring therapeutic approaches to stimulate the immune system better and provide long-lasting protection.²¹

References

1. Szade, K, et al. (2018). Where hematopoietic stem cells live: the bone marrow niche. Antioxidants and Redox Signaling, 29(2), 191–204. https://doi.org/10.1089/ars.2017.7419
2. Filipek-Gorzała, J, et al. (2024). The dark side of stemness – the role of hematopoietic stem cells in development of blood malignancies. Frontiers in Oncology, 14. https://doi.org/10.3389/fonc.2024.1308709
3. Hu, D., & Shilatifard, A. (2016). Epigenetics of hematopoiesis and hematological malignancies. Genes & Development, 30(18), 2021–2041. https://doi.org/10.1101/gad.284109.116
4. Valsecchi, M. C. (2023). Rescue of an orphan drug points to a new model for therapies for rare diseases. Nature Italy. https://doi.org/10.1038/d43978-023-00145-1
5. ZYNTEGLO^TM (betibeglogene autotemcel) | An FDA Approved Gene Therapy. (n.d.). [Online] https://www.zynteglo.com/
6. Home - Libmeldy. (2024). Libmeldy. [Online] https://www.libmeldy.eu/
7. Kean, L. S., & Blazar, B. R. (2024). Major breakthroughs in hematopoietic stem cell transplantation and future challenges in clinical implementation. Journal of Clinical Investigation, 134(8). https://doi.org/10.1172/jci179944
8. Papp, D., Korcsmaros, T., & Hautefort, I. (2024). Revolutionising immune research with organoid-based co-culture and chip systems. Clinical & Experimental Immunology. https://doi.org/10.1093/cei/uxae004
9. Palis, J., & Yoder, M. C. (2001). Yolk-sac hematopoiesis. Experimental Hematology, 29(8), 927–936. https://doi.org/10.1016/s0301-472x(01)00669-5
10. Philadelphia, C. H. O. (n.d.). Development of the Immune System. Children’s Hospital of Philadelphia. [Online] https://www.chop.edu/vaccine-education-center/human-immune-system/development-immune-system
11. Cui, A, et al. (2023). Dictionary of immune responses to cytokines at single-cell resolution. Nature, 625(7994), 377–384. https://doi.org/10.1038/s41586-023-06816-9
12. Cordes, M, et al. (2023). Multi-omic analyses in immune cell development with lessons learned from T cell development. Frontiers in Cell and Developmental Biology, 11. https://doi.org/10.3389/fcell.2023.1163529
13. Neu, S. D., & Dittel, B. N. (2021). Characterization of Definitive Regulatory B Cell Subsets by Cell Surface Phenotype, Function and Context. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.787464
14. Karmaus, P. W. F, et al. (2018). Metabolic heterogeneity underlies reciprocal fates of TH17 cell stemness and plasticity. Nature, 565(7737), 101–105. https://doi.org/10.1038/s41586-018-0806-7
15. Yeo, A. T, et al. (2022). Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression. Nature Immunology, 23(6), 971–984. https://doi.org/10.1038/s41590-022-01215-0
16. Shang, H, et al. (2024). B-cell targeted therapies in autoimmune encephalitis: mechanisms, clinical applications, and therapeutic potential. Frontiers in Immunology, 15. https://doi.org/10.3389/fimmu.2024.1368275
17. Mok, C. C. (2013). Rituximab for the treatment of rheumatoid arthritis: an update. Drug Design Development and Therapy, 87. https://doi.org/10.2147/dddt.s41645
18. Salles, G, et al. (2017). Rituximab in B-Cell Hematologic Malignancies: A Review of 20 Years of Clinical Experience. Advances in Therapy, 34(10), 2232–2273. https://doi.org/10.1007/s12325-017-0612-x
19. Targeted Drug Therapy | Breast Cancer Treatment. (n.d.). American Cancer Society. [Online] https://www.cancer.org/cancer/types/breast-cancer/treatment/targeted-therapy-for-breast-cancer.html
20. Alexander, T., & Greco, R. (2022). Hematopoietic stem cell transplantation and cellular therapies for autoimmune diseases: overview and future considerations from the Autoimmune Diseases Working Party (ADWP) of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplantation, 57(7), 1055–1062. https://doi.org/10.1038/s41409-022-01702-w
21. Mahon, R. N., & Hafner, R. (2017). Applying Precision Medicine and Immunotherapy Advances from Oncology to Host-Directed Therapies for Infectious Diseases. Frontiers in Immunology, 8. https://doi.org/10.3389/fimmu.2017.00688

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