When the body is under pathogenic attack, it is the long-armed dendritic cells in the skin that identify the foreign invaders and instruct the body’s killer cells to fight them. Understanding how these multitalented sentinels operate could be central to producing the next generation of vaccines to combat diseases such as cancer and HIV, according to immunologists at Yale and Harvard who published their findings last August in Nature.

Discovered in 1868 by the German scientist Paul Langerhans, dendritic cells became of interest to immunologists in the 1960s but have only recently revealed their operational secrets. It took a novel imaging approach to observe the role the cells play in precipitating the body’s immune response.

By tagging the relevant molecules with green fluorescent dye, the groups from Yale and Harvard used video imaging of cultured cells to chart the pathway of an antigen, a protein that stimulates an immune response. For the first time, scientists observed molecules moving in a live dendritic cell.

Dendritic cells reside in the skin, constantly feasting on the proteins that surround them. If a foreign antigen is present, it is consumed and transported to an acidic compartment deep within the dendritic cell called a lysosome. Aided by enzymes, the lysosome chops the proteins up into more manageable chunks called peptides. Meanwhile the dendritic cell travels to the killer T cells in the lymph, which ultimately deal with invaders.

But how do peptides get from the enclosed compartment, the lysosome, at the cell’s core—so impenetrable that Yale’s Ira Mellman, Ph.D., chair and professor of cell biology, calls it “Dante’s seventh level”—to its surface, where they can interact with T cells?

Under Mellman’s supervision, graduate student Amy Chow and associate research scientist Derek Toomre, Ph.D., watched the growth of long thin tubules that became the peptides’ escape routes. They begin emanating from the lysosome shortly after a foreign invader is detected, and finally fuse with the cell’s surface. Chow saw the green-glowing carrier molecules drag the freshly chopped peptides along the tubules.

At the cell’s surface, the carrier molecules display their cargo of peptides, flagging those that represent dangerous invaders differently from those that came from the body’s own harmless proteins. T cells respond by self-destructing if the peptide is benign and by propagating if they must unleash their arsenal upon it.

“Dendritic cells sit at a critical nexus, deciding whether to respond or ignore a protein. Most immunologists so far have been T-cell-centric, but T cells can’t do anything unless a dendritic cell instructs them,” said Mellman. “Dendritic cells are like cellular psychiatrists. They bring out the deep-seated problems, wait for them to come to the surface and then interpret them.”

Jacques Banchereau, Ph.D., director of the Baylor Institute for Immunology Research in Dallas, said the unprecedented inside view of how dendritic cells operate offered by the Nature studies could pave the way to a more rational approach to vaccine design.