Immune System Development

The immune system consists of lymphoid organs that can be separated into the primary and secondary immune systems as well as the myeloid and lymphoid cells that arise via hematopoiesis. The primary lymphoid organs are the bone marrow and thymus. These are the sites at which hematopoiesis occurs and immature lymphocytes grow, develop, and differentiate. Briefly, thymus development is induced in endodermal cells of the third pharyngeal pouch by signals produced by neural crest-derived mesenchyme. BMP4 signaling specifies early endoderm development, and FGF family members are important for subsequent thymic cell differentiation.

The secondary, or peripheral, lymphoid organs primarily consist of the spleen and lymph nodes (including associated lymphatic vessels) and play roles in antigen presentation and adaptive immune response initiation. The lymphatic system and spleen arise from the mesoderm and signaling via Lymphotoxin-alpha and -beta Receptors are critical for organogenesis. The spleen arises from mesenchymal cells within the dorsal mesentery and functions in erythrocyte turnover. Lymph node organogenesis is thought to begin with formation of the lymphatic vessels. Early lymphatic tissue markers include LYVE-1 and Prox1, and mature lymphatic vessels express markers such as Podoplanin. Following vessel formation, the lymph node primordium is specified and populated by CD45⁺CD4⁺CD3^- lymphoid tissue inducer (LTi) cells, which interact with local mesenchymal cells through cell adhesion molecules (CAMs). LTi cells are thought to induce development of lymph nodes and Peyer's patches through Notch signaling, Id2-dependent transcription, and retinoic acid-related orphan receptor gamma t (ROR gamma t) signaling.