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The now activated helper T cells seek out B cells that have taken up the antigen with the right receptor. When these antigen-activated helper T cells find these B cells, they communicate with them through what is known as synapse II—the interface between the activated helper T cells and the antigen-activated B cells.

At this interface, another set of signals is exchanged in what is one of the crucial regulatory events in determining immunological memory. The outcome of this encounter determines which of two drastically different destinies a B cell will follow—to produce antibodies or to produce memory.

Some of the B cells stay local and make buckets of antibodies. "This response is a clearance response—you are trying to get rid of the antigen load," says McHeyzer-Williams. Other B cells commit to the memory pathway and begin to develop memory B cells.

The way that the development of memory works is that the B cells committed to the memory pathway move into small localized areas in lymph nodes (known as follicular areas), which develop into germinal centers that witness the prolific expansion of these B cells. During this expansion, the B cells also introduce point mutations into their own antigen receptors. These point mutations sometimes change the affinity of the receptor and occasionally will result in a B cell with a mutated receptor that has a much higher affinity than before.

"What you have done on this micro-scale," says McHeyzer-Williams, "is to accelerate evolution." This process creates memory cell "compartments" that contain cells that are much more effective at fighting off the pathogens for which they are specific.

Inside these germinal centers, the activated helper T cells help sort through these B cells according to their affinity and the highest affinity ones become long-lived memory B cells. Then the helper T cells also commit to becoming long-lived memory cells.

Since the B cells have a much higher affinity for the antigen, they are able to detect smaller amounts of it. And since there are more memory helper T cells around that have the right T cell receptor, the B cells have an easier time presenting the antigen to the correct helper T cells. This means that the memory T cells can be activated rapidly and the overall response can be mounted more quickly. These accelerated kinetics and increased magnitude of the response offers better protection than would be possible without memory cells.

If another challenge does come from a pathogen with the same antigen, the memory B cells and the helper T cells can create a rapid and severe response.

"Now you get a reaction within two to three days that would have taken five to seven previously," says McHeyzer-Williams.

Not All Naïve T Cells are Created Equal

McHeyzer-Williams and his group are particularly interested in the receptors, co-receptors, signaling molecules, and other molecules involved in various stages in the development of immunological memory. If the right signals are absent from Synapse I and Synapse II, there will not be memory cells later.

Using the technique of flow cytometry, it is possible to separate and study sub-populations of cells in the body, or to find that single cell with the defined characteristics of interest. In fact, McHeyzer-Williams has built his career on the ability to find those very rare cells with high fidelity.

Recently, what McHeyzer-Williams and his group found is that not all naïve helper T cells are the same. There is a major division among helper T cells even before they are activated on the basis of a mysterious glycoprotein-anchored protein called Ly6C that either is or is not expressed on their surface. A few years ago, they discovered this distinction almost by accident in naïve helper T cells that have been exported from the thymus but are not yet activated.

There are hundreds of genes across these cells that are different, which is a consequence of the selection process that takes place in the thymus. But none of them were predicted to essentially distinguish between two types of naïve T cells in circulation. This was something McHeyzer-Williams and his laboratory discovered one day in a sweeping experiment in which they subjected naïve helper T cells to every reagent in their freezer.

"There it was," he says. "Fifty percent of the helper T cells in the periphery had Ly6C and fifty percent didn't."

The ligand that binds to Ly6C and the overall function of this protein are not known, though McHeyzer-Williams says it probably modulates receptor responses. However, its presence or absence on the surface of these cells seems to have a major effect on function of the cells. It is a major indicator of how they develop and regulate other cells downstream.

"It looks like the two different types of helper T cells help B cells in different ways," says McHeyzer-Williams.

In experiments in which he and his colleagues transferred only the Ly6C positive helper T cells into a model system and then activated them by challenging with the correct antigen, they saw "buckets" of antibody being produced, McHeyzer-Williams says.

But when they did the same experiment with Ly6C negative helper T cells, they saw antibody production that was only five to ten percent of the norm.

"Ly6C-positive T helper cells appear to be specialized for helping B cells," concludes McHeyzer-Williams.

A New Neighbor and Collaborator

In the slightly more than a year since he has come here, McHeyzer-Williams and his laboratory have managed to get things up and running.

He arrived near the end of 2001 with his core group of two postdocs and one technician, and they all had to wait several months for their new, dedicated flow cytometer to arrive. Once it did, it took a few more months for them to get it running at peak performance.

Shortly after his new instrument was finally on-line, TSRI immunology Professor Hugh Rosen [featured in a recent issue of News&Views] moved into the same contiguous laboratory space and was writing grants and getting his own laboratory started.

After several conversations, McHeyzer-Williams recalls, "I said, 'let's do an experiment together.'" So they did.

They designed an experiment involving T cell selection in the thymus using a chemical that Rosen had and an experimental approach designed by McHeyzer-Williams. When they analyzed the results, they saw something completely new—a result that should be forthcoming soon, as their first paper is currently under review.

"We're very excited about it," says McHeyzer-Williams. "Both of us have started a whole new directions of research that we wouldn't have had."

This is especially exciting, he says, since his previously existing research projects are now back on track after the move. McHeyzer-Williams and his laboratory are actively collecting data, writing papers and grants, and he has four new people starting soon. Last week, in fact, he was preparing to interview one postdoctoral fellow candidate and awaiting the arrival of another. And he says that after six months spent doing experiments, his group is finally at a place where they are really starting to take off.

"Now we have too much to do," he says. "This next 12 months are going to be nuts."


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An illustration of developing protective immunity.
Click to enlarge.


































From an empty lab to up and running in one year. Photos by Jason S. Bardi.