Skip to Main Page Content

New research probes key component of the immune system


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. body reaction to infection 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. Download the image to see an enlarged version. Photo by: Michael Northrop Download Full Image

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.)

Cellular guardians

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.

Modeling disease

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.

Richard Harth

Science writer, Biodesign Institute at ASU

480-727-0378

ASU researcher helps students unleash the power of good design


June 25, 2015

Claire Lauer wants her students to become confident creators of multimedia communications for work and everyday life.

“As seasoned users of visual culture, students often come to the university with the ability to recognize good design when they see it, but they don’t know how to produce it themselves,” said Lauer, an associate professor at Arizona State University who focuses on unlocking that potential. ASU professor of technical communication Claire Lauer Associate professor Claire Lauer recently won the Ellen Nold Award for writing the best article in the field of computers and composition studies. She teaches multimedia writing in the technical communication program in the College of Letters and Sciences at ASU's Polytechnic campus. Photo by: Charlie Leight/ASU News Download Full Image

Lauer, who recently won the Ellen Nold Award for her research on technology-related keywords, teaches in the technical communication programs offered at ASU’s Polytechnic campus and online as part of the College of Letters and Sciences.

“Knowing how to take mountains of data, distill it and visually present it in a rhetorically professional and ethical way that is easy for readers to understand is a literacy skill that is almost essential today,” she said, “for people in the sciences, journalism, business – for anyone who has to communicate in almost any kind of organization.”

Two of Lauer’s courses, TWC 411: Principles of Visual Communication and TWC 414: Visualizing Data and Information, are relevant for anyone wanting to develop their skills in crafting content that harnesses the power of visual design. The classes are open to students in any major.

‘White space is not your enemy’

ASU junior Beth Toci took Principles of Visual Communication in fall 2014 to complement her graphic information technology major in the Ira A. Fulton Schools of Engineering.

“My semester in Claire's classroom taught me about light, color, space, contrast, size, etc., and how each plays an important role in how a design affects the viewer,” Toci said. “I also learned to apply rules like ‘white space is not your enemy’ and ‘err on the side of readability’ to make my designs effective and visually appealing.”

She said she’s now better able to explain her design thought processes and to recognize and describe why a particular design can evoke specific feelings or reactions.

“In a nutshell, Claire taught me how good design holds great power, and gave me the ability to create quality work that can mold an audience to my purpose as a designer,” she said.

Lauer said that what she loves most about her work is that visual literacy is relatively achievable with practice of basic design principles and tools. 

“Learning simple building blocks and being able to name principles students might have known all along but didn’t know how to speak about or replicate, often opens up a whole new realm of meaning-making that can make their communications more rich and complex,” she noted.

Career-changing impact

Paul MacDonald had been working as a self-taught, registered architect when the economic downturn brought construction to a halt.

“In 2009, when the building industry essentially stopped, I worked for a while fixing computers, and decided to go to college and get my first bachelor’s degree,” MacDonald said.

He enrolled in the College of Letters and Sciences’ technical communication degree program and in his junior and senior years took Principles of Visual Communication and Visualizing Data and Information with Lauer.

“Both courses, but particularly Visualizing Data and Information, had a profound effect on my education and career,” said MacDonald, who graduated in fall 2014 and is back in the field of architecture, working as a senior designer at the Scottsdale firm Allen + Philp Architects.

“I work with data sets just about every day. Having the ability to better visualize information, eventually represented or expressed as an object (a building, outdoor space or piece of furniture) makes me a better designer. …

“What we learned [in the course] about presenting information to our audience has also had a positive impact on my work. My presentations to clients and other stakeholders are done with greater clarity and control.”

Award-winning research

As the communication landscape expands, Lauer has centered one strand of her research on documenting and analyzing the terms that scholars are using to describe new kinds of digital work, such as “new media,” “multimedia” and “digital media.”

“In courses and the workplace today, we may be asked to construct communications using HTML, iMovie, Prezi,  Adobe Illustrator, Photoshop, and InDesign; incorporating audio and video clips, images, interactive links and text, with an expectation that attention be paid to color, font, layout, organization, layering and other design elements,” Lauer said.

“So what do we call this kind of composition? How would you describe the faculty member you wanted to hire to teach such a course? If you asked 10 people what they would call it, how many different answers would you get?”

She scoured 20 years of the Modern Language Association (MLA) Job Information List advertisements, looking at the use of 17 technology-related terms used to describe the texts, technologies and composing practices that groups were looking for in new hires from 1990 to 2010.

“I wanted to see what patterns emerged and what the clusters of influence might be,” Lauer said.

The resulting research article was honored with the Ellen Nold Award, presented annually for the best article in the field of computers and composition studies, at the national Computers in Writing conference in Wisconsin in May.

In recognizing Lauer’s work, Kristine L. Blair, a professor of English at Bowling Green State University, noted: “This study is the first of its kind in our field and necessary to understanding how our field is both defined and shaped by these postings.”

What were some of the findings?

The term “computer” is being used less frequently. “Digital” (when describing a field such as digital humanities), she found, is being used more to signal a break from tradition, rather than just conveying the literal notion that a text is digital. And “new media” is frequently used to signal a progressive, cutting-edge professional writing or English degree.

“As a field we won’t always agree on which terms to use or how those terms should be defined, but knowing which terms have fallen in and out of favor, when, and in what contexts, can inform how we lead the way forward through our rapidly changing technological landscape,” Lauer said.

Maureen Roen

Editorial and communication coordinator, College of Integrative Sciences and Arts

602-496-1454