T Cell Nucleus 'Goes a Long Way' When Fighting Off Infections

The cell nucleus goes a long way during an immune response, both literally and figuratively.

New research published in Science Immunology shows that in some white blood cells, this genetic storage facility can travel across the entire length of the cell to help clear out infections, a completely unexpected role for the cell’s largest organelle.

The white blood cells in question are cytotoxic T lymphocytes (CTLs), also known as killer T cells. These “warrior” cells work to kill off infected or cancerous cells in what is both a quick yet incredibly complex process.

“When the killer cell comes to meet its target, it’s all beautifully orchestrated,” says Gillian Griffiths, PhD, chair of the Department of Cell Biology at Yale School of Medicine (YSM) and senior author of the study, which she began while a professor at the University of Cambridge. “It triggers enormous reorganization of all the intracellular organelles that polarize exquisitely and focus on an immune synapse that they form with the cell they’re going to kill. It’s incredibly precise.”

Griffiths and her team wanted to understand exactly when and how all of these events happen relative to each other. It’s well established from earlier research in the Griffiths lab that the centrosome—the organelle responsible for moving the granules full of killing molecules—orients to the immune synapse during a killing event, but they were shocked to find that the nucleus was moving too, and in fact moved sooner than the centrosomes.

The work was led by Yukako Asano, PhD, a research associate in Griffiths’ lab.

“Nobody had ever noticed this before,” Griffiths says. “It’s a remarkable phenomenon.”

From start to finish, it takes a CTL about six minutes to identify its target and deliver a killing blow of granules. While a relatively speedy process compared with other cellular interactions, a lot happens during those six minutes, which Griffiths and her team analyzed using four-dimensional cellular imaging.

“We can use different combinations of markers for the different organelles and combine many observations to draw ourselves a map of events leading to granule delivery, which I wanted to fill in with as much molecular detail as I could,” Griffiths says.

The whole six minutes starts with a flux of calcium as T cell signaling starts. However, after only two to three minutes, proteins that control gene activity, called transcription factors, migrate into the nucleus and prompt it to start churning out chemokines and cytokines, molecules that act as extra weapons the CTL can use to help kill its target. Remarkably, at the same time the nucleus starts migrating across the cell to the immune synapse.

“As the nucleus started to move, that was when the transcription factors started to move. The two seemed to be linked,” Griffiths says. In fact, when Griffiths and the team used gene editing to turn off nuclear movement, the transcription factors couldn’t flood into the nucleus, chemokine and cytokine levels dropped, and the cells couldn’t kill as effectively.

Killing didn’t stop entirely; the cells still had the granules, the primary weapons. But without the extra weapons provided by the early transcriptional burst of chemokines and cytokines, killing was reduced.

“It seems excessive,” Griffiths says. “You’d think there’d be an easier way to turn on transcription than moving the whole huge nucleus, the biggest organelle in the cell, but that’s what we see.”

To understand the reason behind this nuclear movement, Griffiths and her team looked at what happens to the nucleus once it reaches its final destination. They found that the nucleus distorts as it moves, puckering the nuclear membrane to focus directly at the immune synapse.

Other organelles like the Golgi apparatus and endoplasmic reticulum localize to the area as well, forming a highly organized pipeline of cellular machinery: the nucleus churns out the instructions to make chemokines and cytokines, where they are immediately made at the endoplasmic reticulum and then shipped off to the target via the Golgi.

“Any newly synthesized protein that’s due for secretion will be transported incredibly quickly because you’ve moved the nucleus right there,” Griffiths says.

While nuclear movement has been identified in other cellular interactions such as wound healing and even in plant cells, the movement isn’t nearly as dramatic as what Griffiths and her team witnessed with the CTLs.

“The nucleus goes a long way in the T cells,” Griffiths says. “Nuclear polarization is an important step in T cell killing and it’s a remarkable phenomenon that had simply gone unnoticed until we used 4D imaging to create our timeline.”