A war is waging in our bodies. Every day our immune systems have to keep constant vigilance for foreign pathogens. Then at a moment’s notice, they must identify and respond correctly to any of countless enemy microbes that try to invade the body.
“We don’t know ahead of time what we’ll be exposed to, so our immune system has evolved to respond to any possibility,” says Avery August, Microbiology and Immunology. “Our immune system has to distinguish between our own cells and foreign cells. It has to turn on mechanisms to fight the microbes but then balance that by turning them off again later. It has to kill the thing that doesn’t belong in our bodies but make sure it leaves all the things that do belong. How does it do that?”
From Allergies to Asthma to Arthritis
August is trying to find the answers to this question as he and his lab explore the body’s inflammatory and anti-inflammatory responses. He is focusing on the T cell receptor signaling pathway, which T cells use to recognize antigens or foreign agents. Once a receptor recognizes an invader, it sends a signal to the T cell via a kinase, an enzyme known as interleukin-2-inducible (Itk). Through a series of steps downstream, changes in gene expression then drive the T cell to become either an inflammatory cell or an anti-inflammatory cell.
In one study, August and his colleagues are exploring the exact mechanisms controlling that process in inflammatory lung diseases such as asthma. They were able to show that Itk determines the development of both T helper 2 (Th2) cells, which are involved in allergies and allergic asthma responses, and T helper 17 (Th17) cells, which are also involved in asthma, as well as other diseases such as arthritis and psoriasis.
“If you have a Th2-driven asthma then most of the current therapies, such as steroids, will work for you,” says August. “But if you have a Th17-driven asthma, then it’s steroid resistant, and the drugs currently on the market are less likely to work. We’re trying to understand how the immune system decides which type of asthmatic response occurs, as a measure of whether you’ll be responsive to different types of treatments.”
Turning an Immune Response On and Off
Itk is also involved in anti-inflammatory responses. The enzyme is able to determine whether a T cell becomes one of two types of anti-inflammatory cells—either Forkhead Box P3 (FOXP3) positive T regulatory cells or Type 1 regulatory (Tr1) cells. Both types of cells produce cytokines that turn off or dampen the immune response.
“The Itk pathway seems to be a central node for both determining the type of inflammation cells will develop, as well as whether the immuno-suppressant portion of the immune response gets turned on,” August says. “Both have to work. You have to be able to turn on the immune response, but you also have to be able to turn it off again, otherwise you’ll have an autoimmune disease.”
The researchers discovered that Itk activates a protein called Ras, which turns on the Tr1 pathway. “We don’t know yet if Ras affects the Th2 pathway,” August says. “We’re exploring each of these components to find out which one is required for which response. We want to find the molecule or sets of molecules that are important for one cell type and not the other. That will allow us to understand the rules of how Itk regulates all these different cell types. Then we can build a network, and we’ll be able to say, for example, if we want to decrease Th17 cells to get less of an asthmatic response, then we manipulate this pathway and not the other.”
Killer T Cells and Viral Infection
Continuing their exploration of the Itk pathway, the August lab conducted another set of experiments focused on killer T cells or CD8+ cells. During a viral infection, Itk activates T cells that become CD8+ cytotoxic cells, able to recognize and kill other cells infected with the virus. Once they’ve cleared the virus, some of these CD8+ T cells become memory cells. These are involved in immunization; they are long lived and able to immediately recognize and attack the pathogen if it should invade again.
“Normally your body has 100 to 200 cells at any one time that recognize a particular pathogen,” August explains. “That’s why it takes a while for you to respond to a pathogen; it takes time for those cells to increase in number. But when you generate memory cells, you get around 500,000 T cells able to recognize the pathogen. And these cells allow you to quickly respond if you have been previously infected or if you have been vaccinated against that pathogen.”
The researchers found that when they exposed genetically modified mouse models that lack Itk to either the flu virus or the bacteria Listeria monocytogenes, their T cells were still able to develop into effector cells to fight the immediate infection. At the same time, the T cells generated more memory cells much more quickly. “This is exciting because it suggests that we may be able to manipulate the amount of memory cells our bodies make by manipulating the Itk pathway,” August says. “During vaccination, if we can make more memory cells earlier that will increase the efficacy of the vaccine.”
“During vaccination, if we can make more memory cells earlier that will increase the efficacy of the vaccine.”
While the August lab doesn’t develop drugs, pharmaceutical companies have used the research generated by the group to help guide them toward Itk as a drug target. “Without the information we develop with our discoveries, they wouldn’t know which molecule to target,” August says. “Using our information, they chemically synthesize compounds to find one that will inhibit Itk, and then they ask us to determine if it actually functions or has any utility in the disease models we study.”
Asking Why and How
From an early age, August had a natural inclination for science. As a child he constantly questioned the reasons things happened the way they did. “I always asked questions of why,” he says. “As I got older and tried to figure out what I wanted to do with my life, I came to the realization that the people who ask why are scientists.”
Once he had identified his calling, August found his passion for questioning the way things work had the perfect outlet in immunology. “I became fascinated by the immune system,” he says. “All these decisions it has to make—how does it do that?”