The goal of most immunology researchers is to find ways to stimulate healthy immune responses to prevent infection, as well as find ways to prevent hyperactive immune responses that lead to autoimmune diseases and chronic inflammation. To do that though, they first need to know how the system works at a precise level. Penn researchers are contributing to that effort.

In one such study, E. John Wherry, PhD, the Director for the Institute for Immunology, discovered why immune cells ultimately lose a long battle with chronic infections such as hepatitis C or HIV. They used a mouse model of chronic viral infection to map the T-cell response that arises when the immune system is in an extended battle. They found that two distinct classes of virus-specific CD8+ T cells – one expressing high levels of the protein T-bet, the other expressing high levels of the protein Eomes, work together to keep the infection in check.

In fact, the two cell populations appear to have a progenitor-mature cell relationship. The T-bet-expressing cells seem to function as the progenitor cells – that is, stem cells. When these cells divide they regenerate and maintain the pool of virus-specific T cells and they produce mature, terminally differentiated Eomes-expressing cells. The Eomes-expressing cells are more effective at fighting the virus itself, but cannot replicate.

Models showed that if either one or the other cell population is lost, the immune system loses its power to control the chronic infection. If the investigators can find a way to increase the pool of progenitor cells, Wherry thinks they may be able to help patients keep chronic infections chronic for longer.

Working from the other side of the immune system-pathogen battle, Jeffrey Weiser, MD, professor of Microbiology and Pediatrics, and colleagues figured out how bacteria sneak past tight cell barriers to cause infection. Normally, the epithelial cells that line the airway are packed close together, like bricks mortared together in orderly rows. But pathogens such as Streptococcus pneumoniae and Haemophilus influenzae have learned how to break apart the bricks.

Animal cells, including the epithelial cells, have evolved to recognize molecules on the surface of pathogens using proteins called Toll-like receptors. But Weiser's team found that when the epithelial cell's Toll-like receptors bound to microbial surface proteins, the binding caused a down regulation of host proteins that keep the epithelial cells tightly packed. Without those mortar-like proteins, the pathogens were able to slip between the epithelial cells and cause an infection in the tissue behind the protective wall.

In other words, the pathogens had found a way to turn a protective response of the epithelial cells into a dangerous one. If Weiser or other researchers can find a way to interrupt this process, they might be able to reduce the likelihood or severity of lung infections.

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