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120 ParT ONE Principles of Immune Response

or CD8 coreceptor. This is accompanied by the movement of CD4
these cells into the medulla of the thymus. Once in the medullary SP
region, interactions with mTECs support negative selection of
the maturing T cells, ensuring the deletion of autoreactive T CD4+
CD8–
cells from the repertoire. Surviving single-positive (SP) thymocytes HSC ETP DN DP
exit the thymus as mature T cells.
CD4– CD4+
CD8– CD8+ CD8
SP
LINEAGE COMMITMENT CD4–
T-cell lineage commitment is the result of a stepwise develop- THYMUS HUMAN CD8+
4,5
mental program that starts with HSCs in bone marrow. These DN1 DN2
HSCs are already endowed with the potential to differentiate CD34+ CD34+
into T cells when directly transplanted into the thymus. However, CD38– CD38+
these HSCs do not fulfill this fate because they lack the ability CD1A– CD1A– T lineage commitment
to migrate to the thymus. Hence, further differentiation is MOUSE
necessary.
DN1 DN2 DN3 DN4
THE COMMON LYMPHOID PROGENITOR CD25– CD25+ CD25+ CD25–
CD44+ CD44+ CD44 low CD44–
Early in ontogeny, a bifurcation event occurs that gives rise to FIG 8.1 Stages of Thymocyte Development. T-cell development
the common myeloid progenitor (CMP) and the common in the thymus is marked by the progression of cells through
lymphoid progenitor (CLP). The CLP produces T cells, whereas distinct stages of differentiation. The stages are defined by the
the CMP represents the first stage at which the potential for the presence of specific cell-surface molecules that are known to
T-cell lineage is extinguished. At the fate bifurcation event, a correspond with defined epigenetic and transcriptional changes.
series of epigenetic modifications are established in the CMP, The double-negative (DN) thymocyte stage is slightly different
and they silence the lymphoid differentiation program in the between humans and mice, and a simplified depiction of this
cells and further imprint erythroid, granulocyte, and myeloid is shown.
6
potential. In contrast, the CLP program enables its progeny to
develop into T cells, B cells, natural killer (NK) cells, or dendritic
cells (DCs). Again, however, T-cell commitment will only occur
following entry to the thymus, whereas B-cell, NK-cell, or DC KEY CONCEPTS
differentiation occurs in bone marrow and fetal liver without Double-Negative (DN), Double-Positive (DP), and
the need for migration. Single-Positive (SP) Thymocytes
Migration into the thymus is not a random event; hemato-
poietic precursor cells utilize specific homing molecules to • Progressive stages of thymocyte development are identified by the
facilitate this process. A fraction of the circulating CLP subset expression profiles of CD4 and CD8 coreceptors.
−
+
+
−
expresses the chemokine receptors CCR7 and CCR9, as well as • DN (CD4 CD8 ) thymocytes give rise to DP (CD4 CD8 ) and then SP
+
−
−
+
the homing molecule P-selectin glycoprotein ligand-1 (PSGL-1). (CD4 CD8 or CD4 CD8 ) thymocytes.
It is these molecules that enable the recruitment of circulating • CD4 and CD8 T-cell lineage determination is coordinated by the major
histocompatibility complex (MHC) recognition of the T-cell receptor
CLP cells to the thymus. 4 (TCR).
The Early Thymic Progenitor • MHC class II restriction leads to CD4 T cells, and MHC class I restriction
leads to CD8 thymocytes, which then leave the thymus to become
The first hematopoietic cell to seed the thymus is termed the mature CD4 or CD8 T cells.
early thymic progenitor (ETP) cell. ETP cells do not take up
permanent residence in the thymus. Thus they must be continually
generated from HSCs in bone marrow. Upon entry into the
thymus, the B-cell potential of this cell population is extinguished. TCR with binding to major histocompatibility complex (MHC)
However, it still retains some level of multipotency in that it can class II peptide complexes on the cell surface of antigen-presenting
differentiate into NK cells and some myeloid cell populations cells (APCs). CD8 is a coreceptor that assists the TCR with binding
as well as T cells. to MHC class I peptide complexes on the surface of most nucleated
−
−
−
cells in the body. CD3 CD4 CD8 cells are termed DN cells in
Double-Negative Thymocytes reference to the absence of CD4 and CD8. 5
In the thymus, T-cell development progresses from the ETP in Cells of the DN phenotype are quite heterogeneous. In mice,
a highly structured order that is marked by the expression of a differential surface expression of CD44 and CD25 can be used
7
particular set of surface molecules (Fig. 8.1). The earliest stages to divide these cells into four distinct stages. CD44 is a broadly
in this process are characterized by the absence of CD3, CD4, distributed cell surface protein thought to mediate cell attachment
and CD8 expression on the surface of maturing thymocytes. to extracellular matrix (ECM) components or specific cell-surface
CD3 is composed of four distinct chains: CD3γ, CD3δ, and two ligands, including hyaluronate and chondroitin-4 and -6 sulfates.
CD3ε chains. Together, this heterotetramer associates the TCR It thus plays a role in matrix adhesion, lymphocyte activation
and the ζ chain (zeta chain) to generate an activation signal in and lymph node homing. CD25 is the interleukin-2 (IL-2) receptor
T lymphocytes. The TCR, ζ-chain, and CD3 molecules together α (IL-2RA) chain. Homodimeric α chains (IL-2RA) create a
constitute the TCR complex. CD4 is a coreceptor that assists low-affinity receptor for IL-2. CD25 can create a high-affinity