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 (see Chaps. 77, 78, and 79),
the earliest events during which hematopoietic stem cells undergo
lymphoid lineage commitment are less-well understood and still somewhat
controversial. Although the conceptual framework for the questions
of lymphoid commitment has been established largely on studies in
murine species, 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
Acronyms and abbreviations
that appear in this chapter include: B, bone marrow derived; BCR,
B-cell receptor; CLP, common lymphoid progenitor; E, days of gestation;
EBF, early B-cell factor; HSC, hematopoietic stem cell; Ig, immunoglobulin;
IL, interleukin; LMPP, lymphoid-multipotential primed progenitor;
LSK, linnegsca-1+c-kit+; NK, natural
killer; SCID, severe combined immunodeficiency.
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 paraaortic splanchnopleure (PAS), and aorto-gonad-mesonephros
(AGM) regions, then the fetal liver, spleen, and finally the fetal
marrow (see Chap. 6). With each change of
anatomical site the range of hematopoiesis becomes progressively
more complex and similar to that of the adult (Fig.
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. Solid
lines show tissues in which long-term reconstituting, multilineage
definitive hematopoietic stem cells (HSCs) are present. Open
lines show sites where only more differentiated hematopoietic
cells are present (i.e., HSCs are absent), e.g., myeloid and erythroid
cells in yolk sac, thymocytes in thymus. “B- and T-cell
potential” (in ovals) refers to the presence of progenitor
cells in the paraaortic splanchnopleure (PAS) that can generate
T- and B-lymphoid cells when cultured in vitro.
B and T cells are first detected in vivo in fetal
liver and thymus, respectively, at times shown in rectangles.
Not shown here are other sites of hematopoiesis such as omentum,
placenta, and spleen, in which exact onset of human lymphoid potential
is less clear. AGM, aorto-gonad-mesonephros.
When assigning hematopoietic function to each developmental stage, it
is important to distinguish the lineage ...