The Flow of Memory
By Jason Socrates Bardi
"Thy
gift, thy tables, are within my brain
Full charactered with lasting memory,
Which shall above that idle rank remain,
Beyond all date; even to eternity..."
—William
Shakespeare, Sonnet 122, circa 1600.
The memory of the immune system is truly a wonderful thing—one
of evolution's great innovations. It allows us to conquer
many of the common and rare infections with which we are "challenged"
over our lifetimes.
In days past, when people were exposed for the first time
to a virus like variola (which causes smallpox), they would
endure the infection until their bodies had defeated the virus
or they died. If they recovered, they would be immune for
the rest of their lives. Even if "challenged" with another
exposure to smallpox, their immune systems would mount a much
more vigorous defense against the pathogen, fight it off,
and clear it from the system subclinically.
Knowing this, doctors began centuries ago to practice "variolation"
and infect patients with what they hoped was a tiny dose of
smallpox to immunize them against later infection. This led
eventually to the innovation of vaccination, a similar but
much safer practice that was developed in the late 18th century.
Vaccination also took advantage of immunological memory, though
perhaps a slightly distorted memory. If a person is exposed
to a variola, like cowpox or vaccinia virus, he/she will acquire
immunity against the similar smallpox virus.
Today, in the wake of a successful concerted global effort
to eradicate smallpox, it is hard to imagine the excitement
generated by the knowledge that a single shot and a sore arm
could provide a lifetime of protection against such a devastating
scourge. Harder, still, because unlike 200 years ago, we can
now describe the basic biology of how vaccination works, based
on our understanding of immunological memory.
Immunological memory is still not perfectly understood,
though, and there many diseases for which we have no good
vaccines despite sometimes enormous efforts to develop them.
One of the newest members of the Department of Immunology
at The Scripps Research Institute (TSRI), Associate Professor
Michael McHeyzer-Williams would like to change that. He and
his team in their brand-new laboratories on the east side
of campus would like to deepen our understanding of the immune
system's memory mechanisms.
McHeyzer-Williams has worked towards this goal for as long
as he can remember in his professional life. He did his graduate
work with Gus Nossal at The Walter and Eliza Hall Institute
in Melbourne, Australia, isolating and identifying these memory
B cells. Memory B cells are one of the key mediators of immunological
memory and produce a vigorous antibody response to fight off
viral infections to which a person has previously been exposed.
Towards the end of his graduate career, he realized that
there was much more to the picture. "I realized to understand
B cell memory," he says, "one had to understand helper T cell
regulation of B cell memory."
So he spent several years as a postdoctoral fellow at Stanford
University with Mark Davis, identifying and isolating specific
T cells and trying to understand how T cells regulate B cell
responses—work that he continued in North Carolina, as
a faculty member at the Duke University School of Medicine.
"Then I realized that this T cell response that regulates
B cell memory is, itself, regulated by dendritic cells,"
he says. So he and his laboratory started looking at the action
of these dendritic cells, isolating the ones that seem to
be involved in the regulation of helper T cells and asking
how they do it.
McHeyzer-Williams and his laboratory are continuing this
work at TSRI, and they have come to appreciate that since
B cell memory depends on helper T cell regulation, which depends
on regulation of dendritic cells, they must study all three.
"Memory is not one thing," he says. "It's a cascade of events
with a multitude of outcomes."
Dendritic Cells—the Early Regulators
The easiest way to understand immunological memory is to
take a look at the process through which it forms—starting
at the moment when a virus or other pathogen first enters
the body and begins to circulate, infect, and replicate.
Over millions of years of evolution, the immune system has
built up myriad ways of countering such potentially lethal
infections, including a strong first line of defense mediated
by innate immune cells. One of these innate immune cells,
the spider-like dendritic cells, circulate through the bloodstream
or sit in the skin or other organs when they are alerted to
the presence of a pathogen.
Once alerted, they become active. As active dendritic cells,
they mediate the general innate immune response and the clearance
of the pathogens from the bloodstream and infected tissues.
This involves making and releasing inflammatory chemicals
and proteins that attract neutrophils and other "effector"
innate immune cells.
The innate immune response is, however, only half the picture.
The slower and more specific adaptive immune response plays
a critical role in ensuring our survival as well. Activated
dendritic cells play a key role in this response. "They are
the key regulators of everything that follows," says McHeyzer-Williams.
Activated dendritic cells are the intermediary between the
innate and adaptive arms of the immune system, because they
act as "professional" antigen-presenting cells. They take
up bacteria or viruses and process them—chopping their
proteins and other "antigen" components into pieces and presenting
them on their surface in a large assembly known as the major
histocompatability complex. They also move into the local
lymph nodes and show the antigen to naïve helper T cells,
which periodically enter the lymph nodes as they circulate
through the bloodstream.
Helper T cells are one of the crucial players in the adaptive
immune response. They develop in the thymus and circulate
as naïve cells until they "see" the right professional
antigen-presenting cell with their unique T cell receptor,
which is something like a lock with only one key.
When a circulating naïve helper T cell with the right
T cell receptor sees an activated dendritic cell with the
right antigen in its major histocompatability complex, then
that naïve helper T cell itself becomes activated.
Once activated, the helper T cell will produce a swill of
chemicals to clear the infection and attract other immune
cells, like killer T cells and B cells.
"That starts the whole adaptive response," says McHeyzer-Williams.
The T helper cells then turn around and regulate the response.
Synapse I and Synapse II
Borrowing a term from the neuroscientists, immunologists
call the interface between the naïve helper T cells and
the activated dendritic cells synapse I, possibly to evoke
the complex cellular communication processes that are focussed
at this interface through the T cell receptor and the antigen-major
histocompatibility complex.
At this interface, the cells communicate with one another
and transmit information through surface and secreted molecules.
The nature of these interactions regulate the outcome of the
immune response. In the case of naïve helper T cells,
the outcome is their activation.
Once the T cells are activated, all hell breaks loose.
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