Page 212 - Clinical Immunology_ Principles and Practice ( PDFDrive )

192 PART ONE Principles of Immune Response

such “escaped” autoreactive cells in secondary lymphoid organs are deleted. AIRE-deficient humans and mice develop autoimmune
and tissues is achieved through a series of extrathymic processes; polyendocrinopathy–candidiasis–ectodermal dystrophy (APS-1
these are referred to in aggregate as peripheral tolerance. or APECED in humans; Chapter 35), emphasizing the role of
central tolerance in preventing T cell–mediated autoimmune
Central Tolerance/Clonal Deletion disease.
Techniques that allow “fate mapping” of clonal populations during Isolated TRA presentation by mTEC is unlikely to fully account
T-cell development have opened windows into the molecular for successful clonal deletion, given the relative rarity of mTEC
mechanisms of the thymic process of clonal deletion. 34,35 Mono- in thymic stroma and the abundance of autoreactive thymocytes.
clonal antibodies specific for Vβ17 TCR variable regions allow One potential mechanism for enhancing exposure of autoreactive
tracking of developing thymocytes that react with endogenous cells to deleting TRA-driven signals is antigen presentation by
retrovirus-derived “self” peptides. Such peptides form the additional thymic stromal cells. A recent observation that intercel-
dominant antigens for Vβ17-bearing thymocytes. In the normal lular transfer of TRA between mTEC and thymic-resident or
+
+
murine thymus, immature Vβ17-expressing CD4 CD8 (double- migrant DCs readily occurs supports this model. 36
positive [DP]) thymocytes are present, but the fraction of
Vβ17-expressing cells in the mature CD4 single-positive (CD4SP) Peripheral Mechanisms of Tolerance
or CD8SP compartments declines precipitously. The paucity of Clonal deletion, like all biological processes, is imperfect. Given
Vβ17-expressing mature thymocytes thus suggests that clonal the potential for autoimmune tissue damage should central
deletion can occur at the transition from DP to SP. tolerance mechanisms fail (as exemplified in those humans and
TCR transgenic mice expressing a single specificity TCR mice carrying AIRE mutations), there must be “backup” mecha-
potentiated additional investigation into central tolerance. Mice nisms to control autoreactivity of T cells that manage to escape
bearing transgenic TCRs reactive with a Y chromosome–encoded the thymus. These mechanisms include immune privilege, anergy,
antigen (H-Y) are among the oldest models of clonal deletion. and regulation.
Massive deletion of developing thymocytes results in small thymi
in self-antigen–expressing (male) mice; only a small number of Immune Privilege
DP thymocytes avoid the apoptotic cell death induced by TCR Medawar first described the concept of “immune privilege” more
engagement. In contrast, transgenic T cells develop normally in than 50 years ago. Typically described areas of immune privilege
littermate female mice that lack H-Y antigen. Additional TCR include the anterior chamber of the eye, the brain, and the fetus
39
transgenic models of central tolerance have shown that autoreac- in pregnant females. The eye and the brain are critical organs
tive thymocyte deletion can occur before, during, or after the for basic survival functions and yet have a limited capacity for
DP stage. regeneration. Thus uncontrolled immune responses in these
Deletion for self-reactivity implies that the extent of autore- organs could have a detrimental effect on survival. A fetus
activity of the developing thymocytes is systematically calibrated. expresses MHC derived from both parents; thus the mother’s
A currently favored model is one that employs strength of signal immune system must develop tolerance of the paternal antigen–
as determined by a combination of TCR affinity and costimulation bearing fetus to prevent pregnancy loss.
36
to assess the extent of self-reactivity. Signals that exceed an Immune-privileged tissues evade or suppress immune effector
intensity threshold lead to clonal deletion of cells bearing that functions through multiple mechanisms. Cells of the eye, brain,
TCR. This model is supported by data from animals in which and fetal villous trophoblast display low level or absent surface
the signaling machinery has been genetically altered to increase expression of classic MHC class Ia protein. This feature likely
or decrease TCR signal intensity. For example, an increase in protects them from cytotoxic T-lymphocyte (CTL)–mediated
the number of TCR-associated ITAMs (presumably leading to lysis (Chapter 17). Ocular cells express proapoptotic cell surface
increases in downstream signals) enhances clonal deletion in a molecules, such as CD95 ligand (CD95L) and TRAIL (TNF-related
TCR transgenic system. 37 apoptosis inducing ligand) (Chapter 13). These TNF family
For clonal deletion to establish comprehensive self-tolerance, members may contribute to apoptosis of infiltrating CD95-bearing
T cells must come into contact with all potential self-antigens T cells and other inflammatory cells bearing death receptors
during thymocyte maturation. It is easy to recognize how deletion that serve as cognate ligands for TRAIL. In mice, the presence
of cells reactive to MHC and other widely expressed protein of CD95L on ocular cells is critical for the acceptance of corneal
products can occur in the thymus. However, there are also self- allografts. Soluble factors elaborated by ocular DCs likely con-
antigens whose expression is restricted to a specific tissue or tribute to immune privilege. These include the cytokines
developmental time point. transforming growth factor-β (TGF-β) and IL-10, which may
The complex mechanisms whereby clonal deletion of develop- lead to induction and/or recruitment of Tregs, and migration
ing thymocytes reactive with tissue-restricted antigens (TRAs)— inhibitory factor (MIF) that suppresses natural killer (NK)
expressed only in the pancreas or testes, for example—occurs cell–dependent cytolytic capacity. In addition, ocular DCs may
are beginning to be unraveled. Some evidence supports the produce high levels of indoleamine oxidase, an enzyme that
possibility that all TRAs are transported to the thymus by supports Treg differentiation.
36
APCs, such as migratory DCs. Another, non–mutually exclusive
model holds that subsets of thymus-resident APCs may “ectopi- T-Cell Anergy
cally” express TRAs. The leading candidate for controlling TRA Cellular proliferation and/or potentiation of T-cell effector
expression within medullary thymic epithelial cells (mTECs) function are not inevitable consequences of TCR engagement.
38
is the transcription factor AIRE (autoimmune regulator). Under some conditions, TCR ligation results in anergy, a cellular
AIRE expression ectopically drives mTEC to express peptides fate characterized by reduced proliferation and cytokine produc-
40
from open reading frames representing TRA. Self-reactive tion in response to subsequent TCR engagement. T-cell anergy
developing T cells are thus exposed to TRAs in the thymus and can ensue either when the TCR is engaged without concomitant