New Research Targets Immune System Vulnerabilities

CD8 ‘Killer’ T-Cells defending the body against a cancer cell.
A cluster of CD8 ‘Killer’ T-cells defending the body against a cancer cell.
T-cells are the body’s soldiers in the war against disease. A discovery by Physics’ Weiqun Peng may strengthen our immune systems’ army and help fight off the most virulent toxic invaders.
July 13, 2016

By John DiConsiglio

In the battle against infections and diseases, from AIDS to cancer to diabetes, T-cells are the human body’s first line of defense. The white blood cells act like soldiers searching out and destroying invading bacteria, viruses and parasites. Vital to our immune systems, T-cells not only find and kill infected cells, but are responsible for tasks like creating antibodies, naturally eradicating cancer cells and remembering germs our bodies encountered decades ago.

But even the strongest armies sometimes find themselves under siege. When autoimmune diseases and viral infections attack our bodies, they thrive by targeting T-cells—either killing them, disrupting their performance or causing an imbalance in their ranks. With weakened or depleted T-cells, humans can be left virtually defenseless against potentially fatal assaults.

A new study lead by Associate Professor of Physics Weiqun Peng may go a long way toward defending our natural defenders and reinforcing damaged T-cell systems. In a paper published in the journal Nature Immunology, Peng, along with fourth-year PhD student Zhouhao Zeng and immunologists from the University of Iowa, have unlocked part of the mystery behind T-cell identification—how individual T-cells determine what their functions will be. The discovery is an important step toward designing drugs that can correct a depletion or imbalance of T-cells and may help the body’s defense against autoimmune diseases like AIDS.

“Many diseases operate by perturbing the balance between distinct types of T-cells,” Peng explained. “By understanding how these cells are formed, we may, in theory, be able to manipulate T-cell creation and combat autoimmune diseases.”

Helpers and Killers

T-cells are broadly divided into two different categories: Helper cells (also called CD4), which coordinate the immune response to invading infections, and Killer cells (or CD8), which actually destroy infected cells to fight off illnesses. Helper cells send out chemical messages, alerting the immune system that a virus has been detected. The Helper cells instruct the Killer cells to make copies of themselves, creating a CD8 army that then seeks out and eliminates infected cells.

There are 25 million to a billion T-cells in the body. Humans need both Helper and Killer cells to maintain a healthy immune system, with a normal ratio of approximately one Helper cell for every four Killer cells. People with autoimmune diseases tend to have an increased CD4/CD8 ratio, while those with viral infections have a decreased ratio.

Until now, researchers had yet to fully decipher what factors controlled the identity of T-cells—essentially how a cell “decided” if it would be a Helper or Killer. Peng’s team revealed that a complex interplay of proteins called transcription factors are the most vital components in establishing individual T-cell identity. “Think of transcription factors as switches that turn ‘on’ or ‘off’ the genes in our cells,” Peng explained.  Different kinds of cells have different transcription patterns (known as gene expression), making genes more or less active. In the case of T-cells, Peng’s research found that two specific transcription factors—called Tcf1 and Lef1—switched genes “on” and “off” in a pattern that maintained the identity of CD8 Killer cells. If that on/off pattern is disrupted, the cells instead become like CD4 Helper cells. Surprisingly, they found that this feat depends on a previously unknown function of these transcription factors. They have intrinsic enzyme-related activities that can directly influence the epigenetic make-up of cells.

“This significant discovery is a new perspective on gene regulation,” said Zeng, who has worked on the T-cell project since 2014 as a research assistant in Peng’s lab. “Obviously, CD4 and CD8 play important roles in our immune systems. If something goes wrong in the CD4/CD8 mix, our ability to fight off infections and diseases is compromised. But if biomedical scientists can develop strategies to turn on/off the T-cell differentiation pathway, we might be able to make drugs that hit the molecular target" and reinforce our immune systems.

A computational biophysicist, Peng’s role in the project involved analyzing the enormous troves of high-throughput sequencing data generated from experiments conducted by his University of Iowa counterparts. The results of their collaborative research came “as a complete surprise,” Peng said, since, according to conventional wisdom, transcription factors and epigenetic regulators were always thought to be separate entities. After examining numerous scenarios, Peng concluded that Tcf1 and Lef1 were the unexpected determining factors that contain their own epigenetic regulators.

“There were no other options,” he said. “We eliminated all of the possible solutions. When you discount the possible, the only option left is the impossible—or at least what we once thought was impossible.”