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

1332 Chapter 24: The Innate and Adaptive Immune Systems
(discussed in Chapter 15) called Lck, which phosphorylates various intracellular
proteins on tyrosines and thereby participates in the activation of the T cell (discussed
later).
The AIDS virus (HIV) uses CD4 molecules (as well as chemokine receptors) to
enter helper T cells (see Figure 23–17). AIDS patients are susceptible to infection
by microbes that are not normally dangerous because HIV depletes helper T cells.
As a result, most AIDS patients die of infection within several years of the onset of
symptoms, unless they are treated with a combination of anti‐HIV drugs. HIV also
uses CD4 and chemokine receptors to enter macrophages, which also have both
types of receptors on their surface.
Developing Thymocytes Undergo Negative and Positive Selection
T cell development begins when bone-marrow-derived lymphoid progenitor
cells enter the thymus from the bloodstream. There, the cells receive a variety of
signals from thymus stromal cells, epithelial cells, macrophages, and dendritic
cells, which promote their stepwise development into mature thymocytes. At one
step, the progenitor cells are induced to express V(D)J recombinase and begin to
rearrange their TCR gene segments. Soon thereafter, the cells express both CD4
and CD8 co-receptors, and these so-called double-positive thymocytes migrate
inward and interact with thymus dendritic cells or epithelial cells expressing self
peptides bound to class I and class II MHC proteins. If the TCR on the thymocyte
binds with high affinity to these complexes, a strong signal will be transmitted,
causing the cell to undergo apoptosis. This process, called negative selection, is
an example of clonal deletion (see Figure 24–21), and it eliminates thymocytes
that could potentially attack normal host cells and tissues and thereby cause an
autoimmune disease if the cells were to continue to mature and leave the thymus.
If its TCR is unable to bind at all to a self-peptide–MHC complex in the thymus,
the thymocyte will fail to receive the signals it needs to survive and will die
of “neglect;” without the ability to recognize self-MHC proteins, a T cell would
generally be of no use, as T cells can only see pathogen-derived peptides in the
context of self-MHC proteins. Thymocytes that express a TCR that binds with an
appropriate affinity to a self peptide bound to either a class I MHC protein (using
CD8 as a co-receptor) or a class II MHC protein (using CD4 as a co-receptor) will
receive an optimal signal to survive and continue to mature, a process called positive
selection (Figure 24–41). As part of this maturation process, and depending
on the TCR’s preference for class I or class II MHC proteins, the CD4 or CD8 co-receptor
that is not needed is silenced by DNA methylation of the respective gene;
this results in the development of CD4 or CD8 single-positive thymocytes, which
exit the thymus as naïve T cells and enter the recirculating pool of T cells—the CD4
cells as either helper or regulatory T cells and the CD8 cells as cytotoxic T cells.
Although naïve helper and cytotoxic T cells constantly receive survival signals
in the form of self peptides bound to MHC proteins that the T cells bind weakly,
a T cell is only activated to proliferate and mount an immune response if its TCR
binds with high affinity to a peptide–MHC complex and receives co-stimulatory
signals at the same time. Generally, this happens only when the T cell encounters
an activated dendritic cell (in a peripheral lymphoid organ) that expresses
an MHC protein with a foreign peptide derived from a pathogen in its binding
groove. Only then will the naïve T cell proliferate and differentiate into an effector
or memory T cell.
Negative selection in the thymus is a major mechanism for ensuring that
peripheral T cells do not react with host cells expressing MHC proteins with peptides
derived from self proteins in their peptide-binding grooves. This mechanism,
however, requires that the APCs in the thymus display an array of peptides
on their MHC molecules that will reflect the self proteins in peripheral tissues, as
well as in the thymus. The thymus, however, would not be expected to produce
many of the proteins that are specifically expressed in other organs. As an example,
it would not be expected to produce insulin, and yet it is crucial to delete thymocytes
with TCRs that could recognize insulin-derived peptides bound to MHC