June 25, 2015
Like acutely sensitive watchmen, CD8 T cells patrol the bloodstream, ever on guard for suspicious activity.
These cytotoxic – or lethal – cells provide an indispensible line of defense against infection, but it can be a double-edged sword. Their numbers must be held in a delicate balance: Too few will fail to ward off infection, while too many can be lethal.
In a multi-stage reaction to infection, the body uses "killer" T cells to target and destroy infection. When T cells fail to clear an infection (as often happens with cancer, hepatitis C or HIV), they become exhausted and shut down their cell-killing function.
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Indeed, as Joseph Blattman, a researcher at Arizona State University’s Biodesign Institute, pointed out: “Usually, you don’t feel sick from what you’re infected with; you feel sick because of your body’s response to infection.”
In the case of deadly diseases like Ebola, the immune system’s aggressive efforts to kill virally infected cells often help kill the patient.
Blattman and his colleagues are working on a new project to better understand the subtle biological dance that determines whether CD8 T cells will be ineffective, protective or pathologic in response to viral infection. The research may yield vital clues for the design of better vaccines and new treatments for persistent infections, during which CD8 T cells often shut down their activity in a process known as T-cell exhaustion. (Joseph Blattman is also assistant professor with the School of Life Sciences at ASU's College of Liberal Arts and Science.)
Under a five-year, $1.9 million grant from the National Institute of Allergy and Infectious Diseases, Blattman, principle investigator Rustom Antia and Ira Longini will use mathematical modeling verified by experiment to explore the interplay between infectious pathogens and CD8 T-cell response.
(Antia and Longini are researchers at the Department of Biology, Emory University; and the Center for Statistics and Quantitative Infectious Diseases, Emerging Pathogens Institute at the University of Florida, respectively.)
T cells – a type of white blood cell produced in the thymus – form the centerpiece of the body’s adaptive immune system. Like sentinels, they circulate in the bloodstream, vigilantly prowling for infections or cellular abnormalities. While T cells exist in several varieties, two primary forms are critical: helper T cells and killer T cells.
CD8 T cells are killer cells, responsible for targeting hazardous invaders and destroying them. Such killer T cells perform their remarkable feats by identifying aberrant features on the surfaces of infected cells, marking them for annihilation. (Intermediary messengers known as dendritic cells present these cell-surface disease markers to CD8 T cells.)
While killer T cells are essential ingredients in the body’s ability to combat a broad range of bacterial and viral pathogens, they fail to provide adequate protection from certain persistent viral infections, such as HIV or hepatitis C. Thus far, traditional vaccines, which often provide protection through stimulation of T-cell response, fail to engage immune cells effectively to fight these illnesses.
One problem is that CD8 T cells that are unsuccessful at clearing an infection within a certain period act to limit their collateral damage to healthy cells, shutting down hunter-killer activity – a process known as T-cell exhaustion. Having failed to erradicate a hostile invader, the body essentially acts to cut its losses.
The process is similar to the termination of ineffective chemotherapy against cancer.
“The job of the immune system is to make our bodies an inhospitable place for something that infects us – but not so inhospitable that we can’t survive,” Blattman said.
Before a new class of vaccine candidates or therapies can be designed to address currently intractable infections, a much keener understanding of T-cell response to viral invasion will be needed.
The problems involved are too complex, however, to address purely by intuitive or qualitative means. The current project seeks to quantify T-cell response under specific scenarios, developing models for T-cell behavior as it relates to persistent viral infection.
During the course of viral infection, populations of viruses and responding T cells can change more than a thousand-fold in magnitude. Non-linear interactions between pathogens, cells and molecules of the immune response result in intricate dynamics, often difficult to grasp without careful mathematical modeling.
Typically, populations of T cells exponentially expand in numbers in response to infection, and then subsequently contract.
“The hard part,” Blattman said, “is really understanding why most T cells die off, why some survive and, ultimately, how many are needed to protect from infections.”
The current collaboration involves a lively symbiosis of theoretical hypothesis (Antia), experimental validation (Blattman) and statistical analysis (Longini).
Mathematical models are powerful tools for investigating the complex, non-linear interplay between an organism’s immune system and the pathogens that infect it. For the current project, the researchers seek to quantify the response of CD8 T cells to a specific, well-studied viral pathogen known as lymphocytic choriomeningitis virus (LCMV), which commonly infects mice.
The point of exhaustion
LCMV has been the focus of intense and extended study. Many central principles of immune function have been uncovered through the exploration of this model virus.
Blattman explained that the LCMV system is an ideal platform for modeling the parameters of protection and pathology. Precise numbers and properties of T cells can be tracked as well as the details of the host environment, allowing for fine-grained modeling of viral infection and subsequent response.
LCMV is easy to handle and grow in the laboratory. Most importantly, LCMV can naturally infect both mice and humans, improving the ability of mathematical models to more accurately portray infection processes in people.
The research project will focus on developing enhanced models to quantify key variables guiding the infection-response interaction, including proliferation rates of T cells in vivo, death rates of infected cells and the release of cell signaling proteins known as cytokines, which act to suppress viral infection.
T-cell exhaustion will be explored, with particular attention to the multi-stage course of shutdown, during which T cells successively lose function, beginning with proliferation, followed by cytokine release, production of tumor necrosis factor and finally, cytotoxicity.
Resulting insights may then be applied to developing techniques to improve viral clearance while avoiding increased pathology.
The project will also explore the combined use of antiviral drugs and specific antibodies to reactivate T-cell response, testing these approaches in the LCMV experimental system.