Fortifying a formidable fighter
In the legion of agents the immune system marshals to defend against disease and foreign invaders, one warrior has distinguished itself enough to earn the name “killer T cell.” Formally known as the CD8 T cell, this combatant attacks cancer cells, as well as ordinary cells that have become infected with viruses, bacteria or parasites. By understanding the details of how it does its job, Malini Raghavan hopes to find ways of boosting the powers of this capable fighter.
Like any good soldier, the killer T cell doesn’t just charge around willy-nilly, annihilating anything in its path; it responds to commands and signals that help it home in on appropriate targets. In particular, killer T cells are guided by interactions with antigens—molecules that the body recognizes as foreign.
But it’s not quite as simple as that: the offending antigen must first be “presented” to the killer T cell by another immune system cell called the dendritic cell (named for the branching tentacles on which it displays the antigens of pathogens it engulfs, as well as those it picks up from dead, infected cells). This process primes the T cell to recognize its target. From then on, whenever the killer encounters an antigen-containing complex on the surface of an infected or cancerous cell, a receptor on the T cell interacts with the complex, initiating the killing process.
Raghavan is interested in how that all-important complex—made up of antigens from the invading pathogen, plus an escort known as an MHC class I molecule—is assembled inside the cell. One key player is an intracellular shuttle known as TAP, which picks up the antigens and transports them to a way station where they’re loaded onto the MHC class I molecule for delivery onto the cell surface. Other specific and generic cellular “chaperones,” proteins that assist the assembly of other protein molecules, are also involved.
“We’re interested in how, at the mechanistic level, all these components work,” says Raghavan, “because if we can understand that, we can see how the functions of these components—inducing an antiviral or anti-tumor response—can be enhanced.” In addition, many viruses have evolved strategies for evading killer T cells, so insights into how the process works when effective may lead to ideas for circumventing the viruses’ evasive maneuvers.
Raghavan also seeks to understand how dendritic cells recognize antigens derived from dying cancer cells, knowledge that could point to new types of cancer therapies. Recent studies from other labs have shown that treatment of cancer cells with certain chemotherapeutic drugs or ionizing radiation makes the cells more likely to induce anti-tumor immune responses. Following some treatments, dying cells give off signals that appear to prompt dendritic cell activation of T cells. Learning more about those positive signals and how they are generated by dying cells and transmitted to dendritic cells could help researchers figure out how to direct cancer patients’ immune systems to better combat their cancers.
New insights about MHC class I molecules are important, too, Raghavan adds. These molecules, which are encoded by multiple genes, are highly variable in the human population, and other researchers have shown that this variation is associated with response to diseases such as HIV/AIDS. “Certain MHC class I variants are highly protective in fighting infection, while the presence of other variants can actually accelerate disease progression,” Raghavan says.
Research on assembly of MHC class I molecule complexes has shown that the rate and efficiency of assembly differs for different variants. “No one has asked whether these differences in assembly impact immune response to infection and disease outcome,” says Raghavan, “so that’s one thing we intend to do.”
