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Graduate Researcher Studies Cells that Fight Autoimmunity

Graduate Researcher Studies Cells that Fight Autoimmunity

T-cells are crucial to our immune systems, recognizing viruses, bacterial infections and even cancer cells and triggering immune responses that help kill off these and other dangerous invaders.

Jayashree Srinivasan, photo by Vivian Abagiu

This may sound like an easy task – simply spot what is non-human and flag it for destruction. But it isn't. T-cells must first endure a rigorous training camp if they are to make it to the front lines. The training camp takes place in an organ above the heart called the thymus, a cellular educational arena studied by UT Austin graduate student Jayashree (Jay) Srinivasan. Her work to better understand this process could factor into therapies that protect or rebuild immune system functions in cancer patients.

An Educational Process

The thymus is like if UT combined all of its departments, lectures and labs into one classroom, and then had every faculty member display one clipboard of information. On it, a protein. The label: confirmation that it belongs to the human body.

An uneducated T-cell binds to each protein and learns from the educator cell that the protein should never be a target for immune-system enforcement.

The T-cells meander this enormous classroom for about one week, repeating the binding process until they are able to recognize multiple pieces of the 20,000 genes in the human body. Finally, they are ready to test this knowledge in the outside world.

But some cells don't make it that far.

"There's a selection process," said Srinivasan, a cell and molecular biology graduate student and researcher in the Ehrlich lab.

During the fast-tracked education, T-cells are filtered into camps based on how strongly they bind to certain proteins – essentially by how much attention they pay to a particular lesson, she explains.

Some get just what they need and move on. These cells are selected to fulfill their intended purpose: exit the thymus and join the immune system army.

Others get too enveloped into one lesson. They bind to a protein too tightly; they become distracted too early and too deeply.

Unlike in college, these cells do not get off with just a bad grade. Instead they are ordered to self-destruct. That is because these mal-educated T-cells are dangerous if let loose.

But the process is imperfect. Some malfunctioning T-cells slip through the thymus' defenses and begin to wreak havoc on the body.

These escaped T-cells are called 'autoreactive,' and they go on to trigger autoimmunity. They turn the body against itself, flagging human components for destruction instead of invading ones.

Autoimmunity, then, is a case of should-be generals defecting to mutinous traitors. Thankfully the body has a way to stop them.

The same selection mechanism that produces normal and malfunctioning T-cells creates a third type of cell, a sentinel killer called a regulatory T-cell, or Treg.

"The regulatory cells (Tregs) make sure that these autoreactive T cells do not end up mounting an autoimmune response against anything in your own body," Srinivasan said.

Tregs are chosen because they don't bind too strongly, nor too weakly to the proteins they were meant to learn. They fall somewhere in the middle, so the educator cells select them for a different purpose, acting something like a spy to eliminate a criminal before it can execute an attack.

While the Ehrlich lab has already contributed to important publications about this topic, a lot remains for Srinivasan to discover about this complicated, dramatic T-cell education and selection process. And she did not get here overnight. It took multiple positions over several years to gather the traits, knowledge and experience necessary to pursue answers in this field of research.

The Journey to UT

Srinivasan's first step towards this complicated area of scientific inquiry took place in her sophomore year at Shanmugha Arts, Science, Technology and Research Academy in India, when she developed an affection for asking questions about the natural world.

She and her classmates approached their microbiology professor with a silly idea for an experiment: testing a food-disinfecting Indian tradition.

"It was basically just to see why a certain tradition is followed in India, where a certain type of grass is used to disinfect food items," she said. "We were kind of curious, does the grass actually have any anti-bacterial effects? Or is it just some hocus-pocus that our elders had been saying?"

Accepting of curious students, the professor encouraged Srinivasan and the other students to test their hypothesis and look at how the type of grass interacts with bacteria under a microscope.

"Under the microscope we saw that the surface of the grass had these tiny spike-like structures into which the bacteria went and sat," Srinivasan said. "We concluded that this actually makes sense. The grass does help disinfect food but not for the superstitious reasons that people think make it work."

After this introduction to research science, Srinivasan went on to become a research fellow at the Bose Institute in Kolkata, India, where she began her research in immunology. Afterwards, she interned at Cornell in New York, where she applied her knowledge to studying immune responses following a stroke.

Finally, UT offered her a place to pursue her Ph.D. in Dr. Ehrlich's lab, where she combines her passion for basic scientific questions with an interest in immunology.

Educator Cells & Super-Suppressive Tregs

Srinivasan now works on untangling the Treg selection process. And there are two main categories under which her work fits.

Her first set of questions relates to the educator cells – the ones in the thymus that present proteins to T-cells and select T-cells for different roles.

The educators turn out to be a wildly heterogeneous group. Early research in this field found that there were only two main subtypes, but a closer inspection revealed a cascading diversity of types and subtypes. The puzzle now is fitting each cell to its purpose.

"There are so many different subtypes," Srinivasan said, "that we just don't know what exactly mediates Treg selection, or what exactly mediates the self-destruction process."

It may even appear that the thymus went overboard with how many cells types it can use. But according to Srinivasan, since the body doesn't like to waste energy, every cell must exist for a reason.

"You think that this is mind-boggling," she said. "But there has to be a use for everything."

Also under investigation are Tregs from early in life. It turns out that escaped T-cells formed early in life are very autoreactive and especially dangerous to the developing organism. In order to combat this heightened threat, the thymus produces Tregs that have enhanced suppression abilities.

"They are like super Tregs," Srinivasan said. "They can handle anything that's thrown at them."

One reason for the enhanced suppressive ability could be that since early life is vulnerable, it requires heavier artillery to protect itself, a kind of balancing act, Srinivasan said.

"It's just awesome the way our body came up with this mechanism to balance both ends of the world – fighting infections yet preventing autoimmunity," she added.

A study of this balancing act could lead to useful clinical applications in the future, such as restoring compromised immune systems or fighting autoimmune diseases more effectively.

And while applications often take decades to materialize, associate molecular biosciences professor and lab leader Lauren Ehrlich, said Srinivasan has everything it takes to pursue the basic questions that make them possible.

"Jay is joyful in doing her research while staying super determined to get the result that matters," Ehrlich said. "She's got everything it takes to be a rising superstar."
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Wednesday, 28 October 2020

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