T Cell Selection and Maintenance
By Jason Socrates Bardi
"Am
not I
A fly like thee?
Or art not thou
A man like me?"
———William
Blake, Songs of Innocence and of Experience
Insects rely solely on innate immunity to recognize and fight off foreign
infections, but unlike insects, humans have a second part to their immune
system, known as adaptive immunity.
"The adaptive immune system counters infectious agents," says The Scripps
Research Institute (TSRI) Professor Jon Sprent. "It [reduces our] susceptibility
to infection."
Sprent and his colleague in TSRI's Department of Immunology, Associate
Professor Charles Surh, have been studying for a number of years the cells
that act as crucial mediators of this adaptive immune response.
The adaptive immune response is slower than the innate, but it has a
much higher—indeed, exquisite—specificity. Acquired immune response
cells are able to recognize almost unlimited shapes and forms of pathogens
with such discrimination that they can tell the difference between peptides
that vary by only a single amino acid.
Cells of the adaptive immune system are able to do this because they
are, as a population, extremely diverse. The basic strategy of the adaptive
immune system is to make as many receptors as the body is able, but to
keep the number of cells low. The body sacrifices population for the sake
of diversity, so that there will only be a few cells that can respond
well to any particular insult.
This explains one of the chief differences between the adaptive and
the innate immune systems: speed of response. The few cells that do specifically
recognize some part of a pathogenic invader need time to multiply before
they can mount a response. And multiply they do—in abundance. A single
T cell, one of two key players in the adaptive immune response, can proliferate
into a million cells in a matter of days once it has been activated.
T of Edward's Cells the Murderer Shall Be
T cells, so named because they are created in the thymus, are the focus
of Sprent and Surh's studies. Their long-term goal is to understand how
to counter diseases and, perhaps, come up with better and more effective
vaccines. They are particularly interested in the development of the T
cells in the thymus and in how they are maintained in the peripheral lymphoid
tissues.
Development in the thymus occurs through a highly sophisticated mechanism
whereby the thymus sorts out those cells that are potentially useful in
the periphery from those that are not. This is achieved by screening the
cells for their binding affinity for major histocompatibility complex
(MHC) molecules, the receptors that are present on antigen-presenting
cells recognized by the T cells' own receptors. For mature T cells in
the bloodstream, antigen-presenting cells display pieces of pathogenic
invaders (antigens) in their MHC receptors, and this leads to the activation
of T cells that have the right receptor—one that binds that antigen-loaded
MHC tightly.
In the thymus, MHC molecules also play a crucial role, so they must
be recognized by the T cells. However, the purpose of this recognition
is not to activate the T cells, but to select among them based on the
results of the screening. Only a small percentage survive.
"Well over 95 percent of the T-cells that are made in the thymus are
destroyed there," says Sprent.
Negative and Positive Selection
T cells are meant to recognize bacterial or viral structures, but the
test for developing T cells in the thymus is recognizing MHC that is loaded
with "self" antigen. Through two separate selections, the thymus selects
T cells that recognize this self antigen—but weakly—and releases
them into the periphery.
Most developing T cells don't bind to MHC at all, and these are selected
for programmed cell death. Of the remaining cells, those that have been
positively selected for their ability to recognize self antigen, a further
selection takes place. Those that are highly reactive are selected to
die as well. The elimination of these highly reactive T cells is called
negative selection or central tolerance, and is an important complement
to the positive selection because of the volatility of these highly reactive
T cells.
"If these cells were allowed to get out of the thymus, they'd attack
all our self-components," says Sprent. "We'd turn into a giant kidney
allograft."
Cells that recognize self antigen with low affinity are allowed to live
and trickle through to the periphery, where they circulate as mature T
cells. They do not, however, go on to attack self tissue weakly just because
they recognize it with low affinity. Once T cells are outside the thymus,
they are long-lived and circulate while awaiting signals to activate them—during
an immune response to a viral infection, for instance.
Though only a small percentage of the total number of T cells made in
the thymus are released, the thymus makes a huge number of T cells, so
the pool of T cells in the periphery is still large.
This large pool is important to the body's ability to respond to any
insult from a foreign pathogen. The body's diversity of T cells, some
of which will have receptors that recognize molecular components—antigens—of
the pathogen with high affinity, will mediate an immune response upon
encountering those antigens.
Activated T cells fall into two categories. Helper T cells, sometimes
called CD4+ T cells because they display the CD4 protein on their surface,
secrete chemicals that activate the body's other major class of adaptive
immune cell, the B cells. Cytotoxic, "killer" T cells, which are distinguished
by the CD8 protein they display, are responsible for destroying cells
that are infected with pathogens by inducing apoptosis, or programmed
cell death, in those infected cells.
In either case, a range of T cells will recognize any one structure
of foreign pathogen. However, only those T cells that bind with high affinity,
or with great preference, to antigen presented in MHC will become activated
"effector" cells.
"There is a threshold of affinity that a T cell requires in order to
make a response," says Surh. "In order to become a killer, the cell must
be engaged at that high affinity."
Once activated, T cells will proliferate and undergo a massive expansion,
differentiating into helper and killer T cells. And once the T cells do
what they are supposed to do and get rid of the pathogen, they are eliminated—somehow
cleared from the system, except for a fraction of the cells.
"There is a great deal of interest in how these cells are being destroyed,"
says Sprent. "We're interested in the signaling molecules involved [with
keeping them alive]."
What keeps these cells alive are signals that they receive from their
cell surface molecules, telling them to live. Some cells survive and continue
to circulate in the body in a resting state. These cells are kept alive
by the immune system and are called memory cells, and these are able to
mount a much faster and more aggressive immune response to another challenge
with the same pathogen for which they are specific. Memory cells as a
population live almost indefinitely, dividing every so often into daughter
cells.
The researchers are trying to figure out the mechanisms and key regulators
involved in maintaining memory T cells, with Sprent concentrating on killer
T cells and Surh focusing on helper T cells.
One signal that Sprent has already found is the chemokine interleukin-15
(IL-15). Memory killer T cells are kept alive by IL-15 contact, and if
you take away IL-15, the memory cells will die. What keeps memory helper
cells alive is currently unknown.
How T Cells Grow Up and How They Grow Old
The two scientists are also interested in how T cells develop and live
under normal conditions—as naïve T cells, which is what scientists
call mature T cells before they have been activated. When T cells come
out of the thymus, they join a highly regulated pool of cells in the periphery.
The body maintains and regulates its pool of naïve T cells and resting
memory cells. This regulation is different from the regulation that they
are subjected to in the thymus, and it is also different from the regulation
to which previously activated memory T cells are subjected.
"It used to be thought that once T cells develop in the thymus and come
out to peripheral tissues [as mature cells], they just sit and do nothing—just
wait for an antigen. That doesn't seem to be true," says Surh.
In fact, the fate of T cells that have not been activated seems to be
predetermined during their development in the thymus. What happens in
the thymus is crucial for what happens for the rest of the life of the
T cell, whether it expands or dies.
"Whatever they learned there seems to determine how they will behave
[in the periphery]," says Surh.
Sprent and Surh have developed some models that maintain a larger pool
of T cells, and are now trying to discern whether the larger pool results
from an increased production of T cells in the thymus or from an expansion
of naïve T cells in the periphery.
The body has a homeostatic mechanism that maintains the pool of naïve
T cells—a mechanism that takes no cues from the environment. This
homeostasis determines the number and kind of naïve T cells that
are kept in circulation. If T cell numbers drop to low level, the body
senses this and tells remaining naïve T cells to undergo spontaneous
expansion and fill up the body again.
This can be demonstrated quite dramatically by injecting T cells into
in vivo models that have no T cells. The newly injected T cells recognize
the body's need for T cells, and as a consequence, they begin to expand.
Injecting the same T cells into a normal body does not result in expansion.
naïve T cells need at least one chemical signal to maintain their
population. The cytokine IL-7, a growth factor protein that circulates
systemically, seems to be important for determining how many T cells are
kept around. In laboratory models, Surh has observed that increasing IL-7
causes T cells to expand, and removing T cells causes IL-7 levels to increase,
which in turn instructs the remaining T cells to expand, preparing the
body to fend off the inevitable challenges from foreign pathogens.
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