Page 139 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 8 T-Cell Development 121

receptor for IL-2 when associated with CD122, the IL-2 receptor
β chain (IL-2RB), and CD132, the IL-2 receptor γ chain (IL-2RG). TRANSCRIPTIONAL REGULATION OF
IL-2RG is also termed the common γ chain (γ C ), and it can COMMITMENT TO T-CELL LINEAGE
contribute to IL-4, IL-7, IL-9, IL-15, and IL-21 receptor complexes
in addition to IL-2. Activation of the IL-2 receptor pathway Notch
promotes T-cell proliferation. T-cell development is dependent on a number of molecular
In mice, CD44 DN1 cells express CD44 but not CD25 interactions and signaling events mediated by the cells resident
−
+
7,9
(CD44 CD25 ). Thus they are primed for binding to ECM to the thymus. Among these, the Notch signaling pathway is
components or specific cell-surface ligands, but not for cell integral to the generation of T cells. 5,10,11 The highly conserved
proliferation. DN2 cells express both CD44 and CD25 Notch signaling pathway is known to dictate cell-fate decisions
+
+
(CD44 CD25 ) and are thus primed for location and proliferation. in numerous biological systems. Notch receptors are transmem-
DN3 cells express low levels of CD44 and are positive for CD25 brane molecules. In mammals, there are four members in the
+
lo
(CD44 CD25 ). They are thus more mobile while still being Notch family (Notch1–4). Of these, Notch1 expression plays a
primed for proliferation. Finally, DN4 cells lack both CD44 and crucial role in T-cell progenitors.
−
−
CD25 expression (CD44 CD25 ). 8
In humans, the DN precursor cell population can be segregated Notch Ligand
on the basis of expression of CD34, CD38, and CD1a into two Of the two types of Notch ligands, experimental evidence indicates
stages, DN1 and DN2. The DN1 less mature precursors being that the δ-like (DL) family ligands function primarily during
+
−
−
(CD34 CD38 CD1a ), whereas the DN2 more mature DN cells T-cell development. Upon interaction with its ligand, Notch
+
+
+
8
express CD34, CD38, and CD1a (CD34 CD38 CD1a ). CD34 receptors undergo a proteolytic cleavage event that releases the
is a cell-surface glycoprotein that can mediate the attachment intracellular portion of the molecule. This portion then trans-
of stem cells to the ECM or directly to stromal cells. CD38 is locates into the nucleus to mediate transcription of target genes.
also known as cyclic adenosine diphosphate (cADP) ribose Using elegant in vitro systems to dissect the factors that drive
hydrolase. It is a glycoprotein that also functions in cell adhesion, T-cell development, it has been determined that Notch signaling
12
as well as in signal transduction and calcium signaling. Unlike is critical for commitment to the T-cell lineage. Ligation of
most MHC class I genes, which are located on the short arm of Notch1 on hematopoietic progenitors by OP-9 cells expressing
chromosome 6 within the MHC (Chapter 5), the CD1 genes are DL1, as well as by overexpression of active Notch1 in the progeni-
a nonpolymorphic cluster of MHC class I–like genes on human tor cells, promotes T-cell development and suppresses B-cell
chromosome 1. CD1a molecules associate with the β 2 micro- development. Conversely, deletion of Notch1 expression in
globulin and present antigen to T cells through their TCRs hematopoietic precursor cells prevents the development of T
(Chapter 4). However, instead of peptides, CD1a molecules bind cells in the thymus and instead allows the emergence of immature
13
and present lipid and glycolipid antigens. B cells at this anatomical site. Notch signaling alone does not
Commitment to the T-cell lineage is solidified in thymocytes commit a cell to the T-cell lineage, but it works with other
of the DN phenotype. In mice, lineage commitment occurs during transcription factors to imprint the T-cell fate. Importantly,
5
the DN2 to DN3 transition, whereas T-cell lineage commitment some of the transcription factors are targets of active Notch in
+
+
+
is associated with the CD34 CD38 CD1a population of thy- the cells.
8
mocytes in humans. Rearrangement of the TCR β, γ, and δ loci
can be detected at this stage (Chapter 4). The pre-TCR is expressed T-Cell Factor 7
by αβ T-cell precursors to test for TCRβ structural integrity; Notch target genes that encode molecules critical for T-cell
and, most importantly, the cells that pass this checkpoint stage commitment include the transcription factors T-cell factor-7
no longer retain the ability to differentiate into other hemato- (TCF-7) and the TCF-7 splice variant TCF-1, which are both
poietic lineages. encoded by the Tcf7 gene. 14,15 TCF1 is highly expressed in the
ETP population in the thymus and deletion of Tcf7 results in a
reduction in these cells. Overexpression of TCF-1 in progenitor
Fate Commitment cells upregulates the expression of genes linked to the T-cell
After the cells pass through the DN stage, most of the T lineage– lineage and restores T-cell development even in the absence of
committed thymocytes will follow one of two fates. A minor Notch signaling. Hence, TCF-1 is necessary for initiating T-cell
fraction of these cells will express a functional γδ TCR on the lineage development.
surface and be exported into the periphery. But the bulk of the
DN cells will begin to coexpress both CD4 and CD8 on the cell Enhancer Binding Protein GATA-3
+
+
5,7
surface. The CD4 CD8 DP thymocytes constitute the majority Another transcription factor regulated by Notch signaling and
of cells in the thymus. These are the precursors to the αβ T-cell necessary for T-cell development is GATA-binding protein 3
lineage. It is at this stage of development that T-cell progenitors (GATA-3). GATA-3 is a zinc-finger transcription factor that is
finalize the αβ TCR pairing through rearrangement of the TCR required during multiple stages of T-cell development, as well
α loci and then initiate processes (positive and negative selection) as in T-cell function. GATA-3 is expressed as early as the ETP
to eliminate cells with nonproductive or autoreactive TCRs. Less stage and is critical for the development of this cell population.
than 5% of the DP thymocytes survive the selection processes, Loss of GATA-3 does not perturb the early stages of hematopoiesis,
and the cells that endure downmodulate one of the two corecep- including the CLP stage of development, but does yield few, if
tors from the cell surface, yielding either CD4 or CD8 SP thy- any, ETPs, indicating a nonredundant function for GATA-3 in
mocytes. After this stage of development, the SP cells are exported promoting T-cell development. As cells progress from the ETP
from the thymus and enter the periphery as mature CD4 or stage to the DP stage, GATA-3 expression is maintained, and
CD8 T cells. this transcription factor is known to have distinct functions in