The Long Arm of the Immune System

J. Banchereau

Scientific American, November 2002

They lie buried – their long, tentacle-like arms outstretched – in all the tissues of our bodies that interact with the environment. In the lining of our nose and lungs, lest we inhale the influenza virus in a crowded subway car. In our gastrointestinal tract, to alert our immune system if we swallow a dose of salmonella bacteria. And most important, in our skin, where they lie in wait as stealthy sentinels, should microbes breach the leathery fortress of our epidermis.

They are dendritic cells, a class of white blood cells that encompass some of the least understood but most fascinating actors in the immune system. Over the past several years, researchers have begun to unravel the mysteries of how dendritic cells educate the immune system about what belongs in the body and what is foreign and potentially dangerous. Intriguingly, they have found that dendritic cells initiate and control the overall immune response. For instance, the cells are crucial for establishing immunological “memory”, which is the basis of all vaccines. Indeed, physicians, including those at a number of biotechnology companies, are taking advantage of the role that dendritic cells play in immunization by “vaccinating” cancer patients with dendritic cells loaded with bits of their own tumors to activate their immune system against their cancer. Dendritic cells are also responsible for the phenomenon of immune tolerance, the process through which the immune system learns not to attack other components of the body.

But dendritic cells can have a dark side. The human immunodeficiency virus (HIV) hitches a ride inside dendritic cells to travel to lymph nodes, where it infects and wipes out helper T cells, causing AIDS. And those cells that become active at the wrong time might give rise to autoimmune disorders such as lupus. In these cases, shutting down the activity of dendritic cells could lead to new therapies.

Rare and Precious

Dendritic cells are relatively scarce: they constitute only 0.2 percent of white blood cells in the blood and are present in even smaller proportions in tissues such as the skin. In part because of their rarity, their true function eluded scientists for nearly a century after they were first identified in 1868 by German anatomist Paul Langerhans, who mistook them for nerve endings in the skin.

In 1973 Ralph M. Steinman of the Rockefeller University rediscovered the cells in mouse spleens and recognized that they are part of the immune system. The cells were unusually potent in stimulating immunity in experimental animals. He renamed the cells “dendritic” because of their spiky arms, or dendrites, although the subset of dendritic cells that occur in the epidermis layer of the skin are still commonly called Langerhans cells.

For almost 20 years after the cells’ rediscovery, researchers had to go through a painstakingly slow process to isolate them from fresh tissue for study. But in 1992, my co-workers and I devised methods for growing large amounts of human dendritic cells from bone marrow stem cells in culture dishes in the laboratory. At roughly the same time, Steinman reported that he had invented a technique for culturing dendritic cells from mice.

In 1994 it was found that the cells could be grown from white blood cells called monocytes. Scientists now know that monocytes can be prompted to become either dendritic cells, which turn the immune system on and off, or macrophages, cells that crawl through the body scavenging dead cells and microbes.

The ability to culture dendritic cells offered scientists the opportunity to investigate them in depth for the first time. Some of the initial discoveries expanded the tenuous understanding of how dendritic cells function.

There are several subsets of dendritic cells, which arise from precursors that circulate in the blood and then take up residence in immature form in the skin, mucous membranes, and organs such as the lungs and spleen. Immature dendritic cells are endowed with a wealth of mechanisms for capturing invading microbes: they reel in invaders using suction cup-like receptors on their surfaces, they take microscopic sips of the fluid surrounding them, and they suck in viruses or bacteria by engulfing them in sacks known as vacuoles. It was found that some immature dendritic cells can also zap viruses immediately by secreting a substance called interferon-alpha.

Once they devour foreign objects, the immature cells chop them into fragments (antigens) that can be recognized by the rest of the immune system. The cells use pitchfork-shaped molecules termed the major histocompatibility complex (MHC) to display the antigens on their surfaces. The antigens fit between the tines of the MHC, which comes in two types that vary in shape and in how they acquire their antigen cargo while inside cells.

Dendritic cells are very efficient at capturing and presenting antigens: they can pick up antigens that occur in only minute concentrations. As they process antigens for presentation, they travel to the spleen through the blood or to lymph nodes through the lymph. Once at their destinations, the cells complete their maturation and present their antigen-laden MHC molecules to naïve helper T cells, those that have never encountered antigens before. Dentritic cells are the only cells that can educate naïve helper T cells to recognize an antigen as foreign or dangerous. This unique ability appears to derive from co-stimulatory molecules on their surfaces that can bind to corresponding receptors on the T cells.

Once educated, the helper T cells go to prompt so-called B cells to produce antibodies that bind to and inactivate the antigen. The dendritic cells and helper cells also activate killer T cells, which can destroy cells infected by microbes. Some of the cells that have been educated by dendritic cells become “memory” cells that remain in the body for years – perhaps decades – to combat the invader in case it ever returns.

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