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."


Next Page | What Happens When a T Cell is Activated

1 | 2 |



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.













Depiction of distinct populations of epithelial cells in the mouse thymus. Cortical epithelial cells (blue) mediate positive selection of immature thymocytes. Selected thymocytes then enter the medulla, the site where different populations of epithelial cells (including one which is stained red) exist; some of these populations mediate negative selection to eliminate thymocytes that are overtly-reactive to self antigens. The exact function of the medullary epithelial cells stained in red is not known. (Double staining was performed on frozen sections of normal B6 adult thymus using 6C3 and anti-H2-O antibodies.)