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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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Visualization of dying cells in the normal mouse thymus. Thymocytes undergoing apoptosis (red) are widely distributed throughout the cortex (med), whereas they are less frequent in the medulla (med). This and other data indicate that most of cell death in the thymus is due to lack of positive selection rather than from negative selection. (Apoptotic cells are stained using the TUNEL technique.)


Visualization of negative selection. Apoptotic cells (red) are depicted in a situation where nearly all the positive selected cells are designed to undergo negative selection. Thus, in addition to the background apoptotic cells in the cortex (cor), large clumps of dying cells are visible in the medulla (med). (TUNEL staining was performed on TCR V beta 5 transgenic mice in an H2-E+ background where endogenous mammary tumor viral (MTV) antigens mediate negative selection of transgenic thymocytes. )


Rapid clearance of apoptotic cells by resident macrophages. Nearly all apoptotic cells (red) present in the cortex of normal mouse thymus are found inside resident macrophages (blue) indicating that apoptotic cells are rapidly engulfed by nearly phagocytic cells. (Normal mouse thymus was double stained by the TUNEL technique and an antibody to macrophages.)