T cell’s ‘suicide’ handshake could fend off autoimmune diseases

Human T cell
Preventing the formation of T cells that attack healthy tissues starts with signals sent to precursor cells called thymocytes, researchers discovered. (NIAID)

Autoimmune diseases like rheumatoid arthritis and multiple sclerosis occur when immune cells become overactive and attack healthy tissues in the body. Researchers at the Georgia Institute of Technology have discovered a process the body uses to eliminate the T cells that cause autoimmune disorders—a finding they believe could inspire new therapies for these diseases.

The process of killing harmful immune cells starts with thymocytes, which are precursor cells that eventually mature into T cells. The researchers discovered a mechanism by which the body recognizes abnormally aggressive thymocytes and prompts them to commit suicide before they mature into T cells, according to a statement from the university.

They described that mechanism as a “two-handed handshake.” Here’s how it starts: After thymocytes form in the bone marrow, the body checks T-cell receptors (TCRs) on their surface to make sure they’re able to recognize self-antigens, which identify the body’s cells. Then they run the TCRs through a second test to ensure they don’t overreact to self-antigens. Any cell that fails either test is pushed towards suicide.

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The team studied the cell interactions that lead to thymocytes' destruction and discovered a signaling loop. The self-antigen from one cell signals the TCR. If the TCR overreacts, the thymocyte triggers CD8, a sort of lever that tells the thymocyte to die before it matures into a T cell. The researchers described the finding in the journal Nature Immunology.

The Georgia Tech researchers made their discovery by observing proteins in living cells—specifically the level of force they exert to encourage thymocytes to kill themselves. The combination of the TCR’s signal and the CD8 lever from the thymocyte prolonged the handshake between the TCR and the self-antigen, which is ultimately what signaled the immune precursor cell to die. That level of force “is significant for the selection to work,” said study leader Cheng Zhu, a professor of biomedical engineering at Georgia Tech and Emory University, in the statement.

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Understanding cell signaling is a priority in research aimed at combating autoimmune diseases, and there have been other recent discoveries that are adding to the growing understanding of why the body attacks itself. Over the summer, for example, Johns Hopkins researchers discovered that a protein called the Yes-associated protein (YAP), which inhibits cell suicide, also suppresses regulatory T cells (Tregs). Because Tregs are essential for keeping the immune system from spinning out of control, they believe stimulating YAP could be a new way to treat autoimmune disorders.

The Georgia Tech team is also interested in examining whether their work could translate into therapies for autoimmune diseases. The signaling process that determines whether a thymocyte will mature into a T cell or commit suicide takes about two weeks, they estimate—a window that could present an opportunity for intervention. “You don't want the cells with strongly grabbing receptor sites to turn against the body itself,” Zhu said.

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