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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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