Immunity system complexity: new T cell triggers (Introduction)

by David Turell , Saturday, August 19, 2023, 16:40 (252 days ago) @ David Turell

Complex discovery:

https://medicalxpress.com/news/2023-08-major-implications-cell.html

'According to new research in the journal Immunity, T cells have a nuclear receptor doing something very odd—but very important—to help them fight pathogens and destroy cancer cells. This receptor, called retinoic acid receptor alpha (RARα), is known to control gene expression programs in the nucleus, but it also now appears to operate outside the cell nucleus to coordinate the early events triggered at the cell surface that lead to T cell activation.

"Scientists wouldn't normally expect to see a nuclear receptor such as RARα playing this role outside the cell nucleus. And yet the new findings suggest T cells cannot begin to fight disease without a form of RARα on the scene in the cytoplasm.

"'Cytoplasmic retinoic acid receptors turn out to be central for a T cell to link sensing at the cell surface with downstream signaling cascades and gene expression programs that transform the T cell to become an active fighter," says Professor Hilde Cheroutre, Ph.D., who led the new study at La Jolla Institute for Immunology.

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"Special molecules called T cell receptors (TCRs) sit on the cell membrane, where they receive messages from other cells. You can imagine TCRs as fire-spotters, the lookouts who scan for smoke from remote cabins in the wilderness. Just as fire-spotters need to alert officials to any smoke in the distance, TCRs need to quickly signal headquarters—the cell nucleus—if they detect a potential threat, such as a virus or cancer cell.

"Sending that signal to the cell nucleus is critical for activating gene expression to transform the T cell to a fighter cell. But TCRs can't just pick up a phone, so how do they alert the distant cell nucleus to trouble?

"The signaling process is fascinating. Once the TCR is triggered, molecules called kinases (enzymes that add phosphates to proteins) work with adaptors that tell nearby proteins to "click" together and assemble a special molecular "activation complex." This complex is called a TCR signalosome, and it comes together just inside the cell membrane. "The TCR signalosome is extremely important for mediating communication between the outside and the inside of a cell," says Cheroutre.

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"The researchers were intrigued to find that RARα actually comes in two variants, called isoforms. "These isoforms are encoded by the same gene, but they differ a little bit at one end. The consequences however are more significant and lock one form in the cytoplasm whereas the other form is confined to the nucleus" says Cheroutre.

"Could these two isoforms play different roles in T cells? Looking closer, the researchers realized this RARα isoform did not respond to retinoic acid and didn't even have the right equipment to function as a nuclear receptor.

"It didn't have the tools that are important for nuclear receptors, namely the ability to interact with DNA and the ability to translocate from the cytoplasm to the nucleus," says Cheroutre.

"Using CRISPR gene editing techniques to modulate expression of the two isoforms, the researchers found that modulating the cytoplasmic isoform caused major problems for TCR signaling in the cytoplasm and impaired the communication with the control center in the nucleus.

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"For T cells, phosphorylation spurs key proteins into action when a threat is near. "There are hundreds to thousands of dynamic phosphorylation events that occur during the first hour or so of T cell stimulation," says Myers.

"As Myers and his colleagues examined their data, they were surprised to spot a phosphorylation event related to RARα. In fact, phosphorylation of RARα began just three minutes into T cell activation. "Because this event was that early, our findings suggest that this phosphorylation of RARα is near the T cell receptor—and it has a burst in activity right after the TCR is stimulated," says Myers.

"This discovery added to the evidence that the cytoplasmic isoform of RARα is activated by the TCR instead of by RA like the nuclear RARα. Thus, this new form of RARα represents an essential component of the TCR/ZAP70 activation complex at the cell surface.

"Cheroutre and her colleagues then shed light on another fascinating phenomenon in the cytoplasm. Scientists knew that RA, which is present in the blood and taken up by the T cells, is further transported to the nucleus by a molecule called cellular retinoic acid binding protein 2 (CRABP2). CRABP2 in the cytoplasm binds to RA and carries it into the cell nucleus where it activates nuclear RARα.

"The researchers showed that without CRABP2, RA remains in the cytoplasm of the T cell and instead of activating cytoplasmic RARα, it interferes with TCR-activated RARα in the cytoplasm and blocks T cell activation. As a result, the T cell can no longer effectively fight infections or kill cancer cells. The good side of this phenomenon is that the interference of RA with the cytoplasmic RARα reduces the inflammatory response of the T cell. The researchers think this process may make an important target to fight autoimmune diseases and other inflammatory diseases."

comment: The Crispr technique shows how complex the biochemical designs are.