Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

T CELLS AND MHC PROTEINS
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Figure 24–41 Positive and negative
progenitor cell
selection in the thymus. Developing
thymocytes with TCRs that would
potentially enable them to respond to
peptides in association with self MHC
DIVERSIFICATION OF T CELL RECEPTORS (TCRs) ON DEVELOPING THYMOCYTES
proteins after they leave the thymus are
positively selected: the binding of their
TCRs to self peptides bound to self
MHC proteins in the thymus signals such
cells to survive, mature, and migrate to
TCRs with no TCRs with two strong TCRs with appropriate
peripheral lymphoid organs. All of the other
recognition of recognition of
recognition of
thymocytes undergo apoptosis—either
self MHC +
self MHC +
self MHC +
self peptide
self peptide
self peptide
because they do not express TCRs that
recognize self MHC proteins with self
peptides bound or because they recognize
such complexes too well and undergo
negative selection.
The regulatory T cells (T reg cells) that
DEATH BY NEGATIVE SELECTION POSITIVE SELECTION
are positively selected in the thymus are
DEFAULT
(signaled death)
(signaled survival)
called natural T reg cells to distinguish them
from induced T
SURVIVAL,
reg cells, which develop
MATURATION,
in peripheral lymphoid organs from naive
and EMIGRATION helper T cells (T H cells), as we discuss
shortly.
apoptotic cell
T H T H T C T C T reg T reg
no TCRs
expressed
DEATH BY
DEFAULT
T cells in peripheral lymphoid organs
proteins on the surface of insulin-secreting β cells in the pancreas. Any failure to
do so would result in the T‐cell-dependent destruction of the β cells and, as a consequence,
cause type 1 (or juvenile) diabetes.
The mechanism that enables the deletion of all such cells in the thymus
depends on a subpopulation of epithelial cells in the thymus that express a transcriptional
regulator called MBoC6 AIRE m25.64/24.43
(autoimmune regulator). By a poorly understood
mechanism, the AIRE protein promotes the production of small amounts
of mRNA from many genes that encode such “organ-specific” proteins, including
the insulin gene. When the peptides derived from the proteins encoded by these
genes are bound by MHC proteins and displayed on the surface of the epithelial
cells in the thymus medulla, this is sufficient to provoke the deletion of the potentially
self-reactive thymocytes. Mutations that inactivate the AIRE gene cause a
severe multiorgan autoimmune disease in both mice and humans, indicating the
importance of AIRE in self-tolerance.
Cytotoxic T Cells Induce Infected Target Cells to Kill Themselves
Cytotoxic T cells (T C cells), like the NK cells discussed earlier, protect us against
intracellular pathogens, including viruses, bacteria, and parasites, that multiply
in the cytoplasm of a host cell. T C cells kill infected host cells before the pathogen
can escape to infect neighboring host cells. Before it can kill, however, a naïve
T C cell has to become an effector cell by activation on an APC, usually an activated
dendritic cell that has pathogen-derived peptides bound to class I MHC
proteins—a process that depends on helper T cells. The effector T C cell can then
recognize any target cell harboring the same pathogen and expressing some of
the same peptide–MHC complexes on its surface: its TCRs cluster, along with CD8
co-receptors, adhesion molecules, and intracellular signaling proteins (discussed
later), at the interface between the two cells, forming an immunological synapse.
In this process, the effector T C cell reorganizes its cytoskeleton to focus its killing
apparatus on the target cell, secreting its toxic proteins into a confined space
(Figure 24–42); in this way, it avoids killing neighboring cells. A similar synapse
forms when an effector helper T cell interacts with its target cell, except that the
co-receptor is CD4 (Movie 24.11).