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Lymphopoiesis refers to the process by which the lymphoid components of the adaptive and innate immune systems are produced during hematopoietic differentiation. This process begins with the hematopoietic stem cell and continues through progenitor stages down a series of mostly diverging lineage pathways, ultimately resulting in the remarkable diversity and flexibility of the immune system. Although the more terminal events in lymphocyte differentiation and function have been defined in detail (Chaps. 20, 21, 75, 76), the earliest events during which hematopoietic stem cells undergo lymphoid lineage commitment are less well understood and still controversial. Although the conceptual framework for the questions of lymphoid commitment has been established largely on studies in the mouse, experimental systems now exist to better understand how such events are controlled in humans. This chapter summarizes what is known about the ontogeny of lymphoid development and the control of lymphoid differentiation, and it discusses some of the persisting controversies in the field.

Acronyms and Abbreviations

AGM, aorto-gonad-mesonephros; BM, bone marrow; BCR, B-cell receptor; C/EBPα, CCAAT/enhancer binding protein; CILP, common innate lymphoid cell progenitor; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; CT, computed tomography; DC, dendritic cell; DN, double negative; E, days of gestation; EBF, early B-cell factor; ETP, early thymic progenitors; FACS, fluorescence-activated cell sorting; FLT3, Fms-like tyrosine kinase 3; HSC, hematopoietic stem cell; haemopoietic stem and progenitor cells (HSPC); Ig, immunoglobulin; IL, interleukin; ILC, innate lymphoid cells, iNKT cells, invariant natural killer T cells; JAK3, Janus kinase 3; LMPP, lymphoid-primed multipotent progenitor; LSK, linnegsca-1+c-kit+; MAIT, mucosa associated invariant T cells; MHC, major histocompatibility complex; MLP, multi-lymphoid progenitor; NK, natural killer; NKT, natural killer T; PAS, para-aortic splanchnopleura; SCID,severe combined immunodeficiency; SLT, secondary lymphoid tissues; TCR, T-cell receptor; Tdt, terminal deoxynucleotidyl transferase; TECs, thymic epithelial cells.


Blood cells are formed from a succession of sites during embryonic and fetal development, beginning outside the embryo in the yolk sac. Soon afterward, hematopoiesis begins in the embryo proper, initially in the para-aortic splanchnopleura (PAS) and aorto-gonad-mesonephros (AGM) regions; then the fetal liver and spleen; and, finally, the fetal marrow (Chap. 6). With each successive change of anatomic site during fetal development, the range of hematopoiesis becomes progressively more complex and similar to that of the adult (Fig. 74–1).

Figure 74–1.

Timing of lymphohematopoiesis during prenatal development. Shown is the timeline for activity in each site of hematopoiesis in the embryo and fetus of (A) human and (B) mouse. B and T cells are first detected in vivo in fetal liver and thymus, respectively, at times shown. AGM, aorto-gonad-mesonephros; PAS, para-aortic splanchnopleura.

When assigning the functional hematopoietic output to each developmental stage, it is important ...

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