The researchers will use a mouse model of a viral brain infection to determine how immune "memory" T cells can successfully clear the virus from infected brain cells, without harming the brain cells themselves. If researchers can define the minimum immunological conditions necessary to achieve this feat in experimental animals, the research would facilitate the development of "immunocytotherapies" to safely rid infected humans of potentially deadly brain viruses.
The brain is a relatively "immune privileged" site that possesses mechanisms to dampen immune defenses. Scientists speculate that this situation may have evolved to protect the brain from the potentially damaging effects of a severe immune response. In the brain, the generation of new replacement cells is minimal compared to cell regeneration in the rest of the body. Consequently, this trade-off may have been evolutionarily necessary to preserve brain functioning.
As a result, however, a number of viruses such as HIV, herpes, measles, and adenovirus manage to invade and infect the brain, without being attacked by the immune system. Interestingly, the investigators have discovered in an animal model that immune cells taught to attack a specific virus can be infused into the animal, and subsequently eliminate the virus without killing the brain cells that the virus has infected. These investigators now will determine how the immune T cells accomplish this extraordinary task. This would be an important step toward development of a new therapeutic strategy to treat viral brain infections in humans.
The investigators will use mice infected from birth with lymphocytic choriomeningitis virus (LCMV). This virus affects humans as well as mice, and has the potential to cause deadly brain meningitis. The immune systems of the mice infected from birth, however, do not recognize the virus as foreign and do not attack it. In contrast, mice that are infected with the virus sometime after birth develop an immune response to the virus. In these mice, certain immune cells, called "memory" T cells, learn to recognize the virus. These memory T cells then remember what the virus looks like and attack it whenever it returns. The researchers have infused these "memory" T cells into the brains of the mice that are infected with the virus from birth. This process is called "adoptive transfer." The researchers found that the adoptively transferred memory T cells eliminated the virus from the animals brains without killing the brain cells harboring the virus. This took 100 days and 357,000 memory T cells, but the investigators do not know how the memory T cells actually accomplished this feat.
Now, the investigators will conduct five studies to learn what occurs between the adoptively transferred memory T cells and the brain cells that harbor the virus. They will use high-resolution microscopy to determine how the infected brain cells send a signal about their plight. Next, the investigators will pinpoint movements and locations of the memory T cells, to establish when the maximal interactions occur between the memory T cells and virus-infected brain cells. Then the researchers will evaluate the interactions between the immune T cells and the virally-infected brain cells at these times. Since the T cell's membrane undergoes substantial reorganization when it engages with a virally infected cell, the researchers will be able to quantify the number and characterize the nature of the T cells' interactions with the infected brain cells.
Thereafter, the investigators will identify the specific chemicals (called cytokines) that immune cells release to kill the virus, and determine whether the T cells directly release these cytokines or instruct other immune cells to release them. Finally, the researchers will determine whether two types of memory T cells, which target different regions of the viral protein, are sufficient to rid the brain of the virus via this adoptive transfer technique.