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.


Next Page | Single, Activated T Cell is Seeking B Cell With Right Receptor

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Associate Professor Michael McHeyzer-Williams is one of the newest members of the Department of Immunology. Photo by Michael Balderas.