Trained to spot and attack foreign invaders anywhere in the body, cells of the immune system must be prepared to strike at the first sign of trouble. But the enemy can be hard to recognize: Is that a deadly virus, or dogwood pollen? Cancer cells, or cat dander?

In each new engagement, a fresh set of immune recruits must size up the enemy and choose the right plan of attack. But if for any reason they falter in the line of duty--the environment grows toxic, say, or scrambles bio-chemical orders meant for the recruits--the results can be disastrous, ranging from the self-destructive "friendly fire" of autoimmune disease to illness or death from infections or tumors.

Laurie Glimcher, the Irene Heinz Given Professor of Immunology, and her colleagues at the Harvard School of Public Health are interested in preventing these sorts of catastrophes. By illuminating the molecular chain of command used by helper T cells, the field commanders of the immune battle, Glimcher hopes to combat diseases like arthritis, allergies, and atherosclerosis.

On the warpath
Helper T cells take their marching orders from specialized immune cells called dendritic cells, whose job is to display foreign proteins. Upon meeting, the two types of cells establish physical contact, which allows them to pass chemical signals over a gap called the immunological synapse. Depending on the message they pick up, the T cells will morph into either Type 1 helpers (TH1), which incite inflammation--a broad, imprecise immune response akin to carpet bombing--or Type 2 helpers (TH2). The latter direct the production of antibodies, which mark foreign invaders for destruction in a targeted stratagem akin to hand-to-hand combat.

To get a look at the events that normally send T cells down one path or the other, Glimcher and research fellow Roberto Maldonado used video microscopy to peer inside the immunological synapse just as T cells and dendritic cells united. Using colored tags to follow a variety of messenger molecules as they moved around on the T cells' surface, the scientists discovered that T cells destined for TH1 status summoned one particular group of molecules into the synapse, while T cells bound for the TH2 pathway called forth a different set.

But what happens when this signaling goes awry, as in disease states, upsetting the balance of TH1 and TH2? TH1 cells are essential for fighting off infections and tumors, but too many TH1s can lead to excessive inflammation, the underlying cause of diseases from arthritis to atherosclerosis. When TH2 cells proliferate or become hyperactive, allergies and asthma may result.

Hope for new therapies
The search for ways to fine-tune helper T cells to treat diseases picked up steam four years ago, when Glimcher discovered a protein that regulated the seesaw balance of TH1 and TH2 production. When she and her HSPH colleagues bred mice that were genetically engineered to make more of the protein and tip the balance slightly in favor of TH2 production, they found that the rodents were protected from developing atherosclerosis. This work, reported with vascular biologist Andrew Lichtman at Harvard Medical School in February, showed that the mice were benefiting from both a decrease in inflammatory TH1 cells and an increase in protective anti-bodies, a TH2 function. These findings raised hopes that Glimcher's research on T helper cell pathways will eventually translate into new treatments for human diseases.

The immune system could face its ultimate test in a war waged with bioterrorist agents like anthrax or smallpox. But Glimcher hopes to cover even that scenario one day. In 2003, her lab received $20 million from the National Institute of Allergy and Infectious Diseases to find ways of bolstering immune defenses against pathogens both familiar and new.

Pat McCaffrey is a freelance journalist who writes about biology and medicine.