Thymocyte and TEC differentiation are interdependent
Early stages of
thymocyte differentiation occur in the cortex where thymocytes interact with
cortical TECs (cTECs) that provide essential signaling molecules for thymocyte
differentiation, proliferation, and survival (9, 10). The stereotypical
migration of these cells within the thymus suggests that TEC subsets in
specific locations throughout the thymus supply different signaling molecules
that promote thymocyte maturation. TECs play an essential role in shaping the T
cell repertoire by presenting self-peptide/MHC complexes that positively or
negatively select thymocytes, resulting in T cells that are self-restricted,
i.e. respond to foreign peptides in the context of self-MHC molecules on
antigen presenting cells (APCs), and self-tolerant, i.e. fail to mount an
immune response to self-peptide/MHC complexes on APCs . Positive selection
occurs in the cortex where CD4+CD8+ thymocytes bearing
TCRs with moderate affinity for self-peptide/MHC complexes presented by cTECs
are rescued from programmed cell death, terminate either CD8 or CD4 expression
and migrate into the medulla (reviewed in (23)). In the medulla,
self-peptide/MHC complexes on mTECs and DCs signal thymocytes with high
affinity TCRs to undergo apoptosis. This negative selection process purges exported
T cells of many self-reactive clones that are capable of causing autoimmunity
(24). It is now well established that mTECs play an indispensable role in
establishing central tolerance and preventing autoimmunity due to their unique
ability to express tissue restricted antigens (TRAs) (25). In addition, mTECs
transfer self-epitopes to dendritic cells which are highly efficient in
inducing central tolerance (13, 14, 26). Expression of a wide array (but not
all) TRAs by mTECs is a regulated by the Aire (autoimmune regulator)
gene (27). Expression of Aire and its target TRAs provide an essential
deterrent to autoimmunity since patients or mice deficient in Aire develop
multiorgan autoimmune disease. In addition, TRAs presented by mTECs promote the
development of CD4+CD25+Foxp3+ T regulatory cells and NKT cells both of which
actively repress self-reactive peripheral T cells (28-30).
Just as TECs are
indispensable for thymocyte development, thymocyte-derived signals are required
for the generation of functional cortical and medullary thymic epithelial
compartments (reviewed in (31, 32). Mice in which thymocyte development is
blocked at or prior to the CD4-CD8-CD44+CD25+
(DN2) stage have severely hypoplastic thymi with a highly disorganized
epithelial compartment that is arrested at an immature developmental stage
characterized by co-expression of keratin 8 (K8) and K5 and lack of a
three-dimensional meshwork (33, 34). In contrast, mice in which thymocyte
development is blocked at the later CD4-CD8-CD44-CD25+
(DN3) stage have a well-organized cortical epithelial compartment that contains
both K8+K5- and K8+K5+ TEC subsets (33, 35, 36) although it is not completely
mature (37). Thymocyte-derived signals are also required for mTEC formation.
Development of the medullary epithelial compartment is severely impaired when
thymocyte development is blocked at or prior to the CD4+ CD8+ double positive
(DP) maturation stage (38, 39). This suggests that signals from positively
selected thymocytes play a role in development and/or expansion of mTECs in the
adult thymus. In the fetal thymus, signals from lymphoid tissue inducer (LTi)
cells are required for initial differentiation of Aire expressing mTECs (40).
Both mature SP thymocytes and LTi cells express ligands that activate members
of the tumor necrosis factor (TNF) receptor superfamily including receptor
activator of NFkB (RANK), CD40 and lymphotoxin-b receptor (LTbR) which are expressed on TECs (41-44). The absence of these
receptors, their ligands or components of the downstream signaling pathways
impairs mTEC development and organization resulting in defective central
tolerance and the appearance of autoimmune disease.
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