By David N. Leff

What with national deficits and surpluses, not to mention proposed tax reforms, a trillion ain't what it used to be.

In scientific notation, that hefty number is expressed as 10¹², and verbalized as "ten to the twelfth power." Tack on three more zeros and you get one quadrillion (10¹⁵), which, so far, is less relevant to politicians than it is to astronomers - and immunologists.

"As the immune system's T lymphocytes develop in the thymus gland," research immunologist Andrew Caton observed, "they generate their T-cell receptors by randomly rearranging mini-genes. There are estimates based on things that may happen during random DNA rearrangement that the immune system can generate as many as 10¹⁵ different T-cell receptors - i.e., that quadrillion."

The thymus gland perches high in the chest, just above the heart. There it matriculates the constant influx of naive T cells given birth by the distant bone marrow. It turns these thymocytes out as finely trained special forces, armed to repel or destroy the infectious, invading viruses and bacteria that flesh is heir to.

Caton, a faculty member at the Wistar Institute in Philadelphia, explained: "The Human Genome Project informs us that we humans have 30,000 genes expressing at least 30,000 proteins, probably more. They can be spliced and processed differently, but those gene products are the proteins that are us - that constitute our bodies. The immune system constantly throws off 10⁸ T cells a day - 100 million. Each of these has different receptors on them, designed to recognize proteins that come from viruses and bacteria."

Thymic T-Cell Library Confronts Universe Out There

"T cells have the potential to generate billions of different receptors," Caton pointed out. "The thymus does this in order to amass a library of T cells with the potential to recognize and react to an unknown pathogen. It's constantly generating these receptors because it has no idea of what the universe it might encounter is going to be outside of the body, what kinds of agents will come in.

"Many of the T-cell receptors it generates," he went on, "are capable of recognizing our own human proteins. Those are the self-reactive T cells, and in healthy people our bodies do a good job of identifying them.

"Until our just-published study," Caton continued, "it identifies and deletes them, tells them to die as they develop in the thymus."

Caton is senior author of a paper in Nature Immunology for April 2001, titled: "Thymic selection of CD4⁺CD25⁺ regulatory T cells induced by an agonist self-peptide."

"We have been able to show for the first time," he told BioWorld Today, "how the immune system generates T-cell subsets whose job it is - instead of responding to infections - to prevent immune responses to ourselves. There's been emerging evidence in the last few years that such T cells exist, but how the immune system generates them hasn't been known.

"So we were able to identify how an interaction with a known self-protein, one of a mouse's own proteins," he related, "educates the cells as they mature in the thymus, and leads them to their export as regulatory cells that prevent autoimmunity. This is a special subset of T cells devoted to this purpose. We estimate that probably something around 10 percent of the T cells in a normal healthy animal are this kind of self-saving regulatory T cell. That's a very large number, but there has been no idea as to how they were being generated.

"The reason these T cells receive so much interest is the prevalent idea that the majority of self-reactive T cells are physically deleted as they develop in the thymus. There they interact with the self-peptide, and that leads to their undergoing programmed cell death in response. That idea has held that the reason people develop T-cell-mediated autoimmune diseases is that there has been some failure in the ability of the body to efficiently delete the autoreactive T cells.

"We showed," Caton went on, "that there's an alternative to deletion. Rather, the body makes regulatory T cells that seem to have exactly the same kind of interaction with self-peptides as one would get in the cell destined to be deleted. Instead they're converted into a regulatory cell - no longer a threat to the autoimmunity - and exported to the periphery, where, if they encounter that self-peptide, their response is to shut down the local immune response.

"The periphery," Caton pointed out, "encompasses all your tissues, your cells, your organs. It's outside the specialized environment of the thymus where the T cells go through these education processes."

Receptor, Spare That Self-Cell!

"That is," Caton added, "a substantial subset of the cells, instead of being told to die, are modified in a way that changes their response to stimulation. Normally, as a T cell goes out into the periphery and encounters a virus-infected cell, and it has a receptor that recognizes that virus, it will help the immune system kill that cell, and clear the virus out of the body. But these regulatory T cells, instead of doing that, when they encounter peptides that are coming from your own tissues, and recognize those, they say: 'Don't attack this self-cell!' and they stop other cells from attacking it."

The co-authors achieved that very effect in transgenic mice engineered to deploy regulatory rather than autoreactive T cells.

"This was very exciting," Caton recounted, "and now we're trying to generate regulatory T cells outside of the thymus, where we could, hopefully, use them to treat autoimmune diseases such as diabetes, rheumatoid arthritis, multiple sclerosis or lupus.

"Autoimmune diseases are caused by active proliferative immune responses to one's own proteins," Caton added. "So we are trying to find ways to manipulate these regulatory T cells, giving us the opportunity to think about introducing them into patients with unwanted autoimmune responses.

"And if we can find ways to generate them," he concluded, "to expand and target them in those people, we could get a more specific way of shutting down immune responses. That would be our hope." n