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T-Cell Development

Laurie E. Harrington

T cells and B cells (Chapter 7) are the two major components further exemplifies the central role of the thymus in T-cell
of the adaptive immune system. T cells are instrumental for development in humans. Patients who develop DiGeorge syn-
protective immunity to numerous pathogens, yet these cells are drome (Chapter 35) as a result of deletions in chromosome
also linked to the pathogenesis of multiple autoimmune disorders. 22q11 and patients with the rare FOXN1 deficiency are both
One aspect unique to T-cell development as opposed to other unable to generate a complete thymus, and both types of patients
hematopoietic cells, including B cells, is the requirement for the exhibit the immunodeficiency associated with decreased peripheral
thymus (Chapter 2). Defective generation of the thymus manifests T cells. In both human conditions, transplantation of thymic
2,3
as reduction in T-cell numbers and resultant T-cell immune tissue is able to restore T-cell development and function.
deficiency (Chapter 35). T-cell development begins with hema- Collectively, these observations demonstrate the fundamental
topoietic stem cells (HSCs) in the fetal liver and later in bone need for the thymus in the generation of mature, peripheral T
marrow. T-cell progenitors then travel to the thymus, where they cells.
undergo a highly intricate and defined series of differentiation The anatomy of the thymus provides the unique microenviron-
steps that ultimately culminate in the mature peripheral T-cell ment necessary to support T-cell development. The thymus is
population. The process of T-cell development is dependent on home not only to T-cell precursors but also to various stromal
several signaling events and cellular interactions. Ultimately this cell populations, including endothelial cells, fibroblasts, and
process provides the host with the diverse repertoire of T cells importantly thymic epithelial cells (TECs) that are fundamental
needed for the recognition of a wide array of ancient and novel to the selection of functional T cells. TECs are not hematopoietic
antigens (Chapters 4 and 6) and for the subsequent generation in origin and require the transcription factor FOXN1 for develop-
of effective adaptive immune responses toward those antigens. ment. This helps explain why FOXN1 is central to thymus
organogenesis and T-cell development and why transplantation
KEY CONCEPTS of the thymus, but not bone marrow, will overcome the T-cell
defect caused by FOXN1 mutations.
Early T-Cell Development The thymus is divided into outer and inner regions, which
are termed cortex and medulla, respectively (Chapter 2). These
• Peripheral T cells are the progeny of hematopoietic stem cells (HSCs) distinct areas foster specific aspects of T-cell commitment and
from bone marrow or fetal liver.
• T-cell development occurs in and requires the thymus. differentiation. This can be partially attributed to the TECs
• Patients without a thymus as a result of FOXN1 mutations or resident to those regions: cortical thymic epithelial cells (cTECs)
DiGeorge syndrome lack circulating T cells. and medullary thymic epithelial cells (mTECs). The cTECs and
• Early thymic progenitors (ETPs) are the first cells to seed the thymus. mTECs can be distinguished by their location within the thymus,
• T-cell lineage commitment requires: the expression of certain proteins, and distinct cytokines and
• Notch signals chemokines that facilitate development of a diverse repertoire
• Upregulation of lineage-defining transcription factors
• Progression through the double negative (DN) stage of mature T cells and deletion of autoreactive T cells.
• T-cell formation requires production of functional αβ or γδ T-cell receptor Development of T cells in the thymus is a precisely orchestrated
(TCR) process involving interactions with specific cell types in specific
locations. (The molecular and cellular cues that shape T-cell
development and selection will be discussed in detail later in
THYMUS: THE SITE OF T-CELL DEVELOPMENT this chapter.) T-cell precursors from the circulation first enter
the thymus via vessels at the corticomedullary junction. Guided
T-cell development is dependent on the presence of the thymus. by cues from stromal cells, such as cTECs, these immature
1
In its absence, the generation of T cells is severely impaired. thymocytes traffic into the cortex area, where commitment to
Whether the absence of a thymus is the result of a germline the T-cell lineage occurs. As thymocyte differentiation progresses
mutation or of surgical removal at the time of birth, peripheral through the double-negative (DN) stage, the cells migrate further
T cells do not develop in mice that do not have a thymus. For into the cortex, to the subcapsular region. Upon rearrangement
example, nude mice lack a thymus and lack T cells. However, of the αβ T-cell receptor (TCR), double-positive (DP) thymocytes
when bone marrow from nude mice is transplanted into mice can be found interspersed in the cortex area, where interactions
with an intact thymus, T-cell development and function are with cTECs mediate positive selection. The DP thymocytes that
restored. Similarly, the genetic disorder DiGeorge syndrome survive positive selection begin to downmodulate either the CD4

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