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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Investigators Jon Sprent and Charles Surh study T cells, with the long-term goal of understanding how to counter diseases and, perhaps, come up with better and more effective vaccines. Photo by Jason S. Bardi.