Lymphopoiesis refers to the process by which the cellular components of the immune system (i.e., T cells, B cells, and natural killer cells, and certain dendritic cells) 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. 75 to 77), 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 discusses some of the persisting controversies in the field.
Acronyms and Abbreviations
AGM, aorto-gonad-mesonephros; BM, bone marrow; BCR, B-cell receptor; CLP, common lymphoid progenitor; CT, computed tomography; DC, dendritic cell; DN, double negative; E, days of gestation; EBF, early B-cell factor; FACS, fluorescence-activated cell sorting; FLT3, Fms-like tyrosine kinase 3; HSC, hematopoietic stem cell; Ig, immunoglobulin; IL, interleukin; JAK3, Janus kinase 3; LMPP, lymphoid-primed multipotent progenitor; LSK, linnegsca-1+c-kit+; NK, natural killer; PAS, para-aortic splanchnopleura; SCID, severe combined immunodeficiency.
LYMPHOPOIESIS DURING PRENATAL DEVELOPMENT
Blood is 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, spleen, and finally the fetal marrow (Chap. 7). With each change of anatomical site, the range of hematopoiesis becomes progressively more complex and similar to that of the adult (Fig. 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 hematopoietic function to each developmental stage, it is important to distinguish the lineage “potential” of stem and progenitor cells that arise from certain areas (i.e., the ability to generate specific lineages in vitro from immature cells removed from a region) from the spontaneous physiologic production of lineages in each region. With this distinction in mind, the onset of lymphopoiesis during embryogenesis lags behind development of the myeloid and erythroid lineages. Although myeloid, erythroid, and natural killer (NK) ...