Ball lands in the cup; cup triggers spring; spring clamps lever onto the ball and holds it tight. That is a rough description of newly discovered cellular mechanisms that eliminate T cells that may cause autoimmune disorders.

Although the mechanisms are intertwined with biochemical processes, they also work mechanically, grasping, tugging and clamping, say researchers at the Georgia Institute of Technology, who, for a new study in the journal Nature Immunology, measured responses to a physical force acting upon these elimination mechanisms.

The mechanisms' purpose is to make dangerously aggressive developing immune cells called thymocytes kill themselves to keep them from attacking the body while sparing healthy thymocytes as they mature into T cells.

Understanding these selection mechanisms, which ensure T cells aggressively pursue hordes of infectors and cancers but not damage healthy human tissue, could someday lead to new immune-regulating therapies.

Two-handed handshake

Usually, researchers pursue such mechanisms using chemistry experiments, but Georgia Tech's Cheng Zhu, who led the study, makes atypical discoveries via physical experiments to observe effects of forces between key proteins in living cells.

"Experiments where the proteins are isolated and used in chemical reactions in vitro miss this force dynamic," said Zhu, a Regents Professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

"Before our work, a force was not considered as a factor in thymocyte selection and now it is," said Zhu. In this study, they discovered a loop of physical signals resembling a double-handed handshake that encourages cell suicide. It is described in more detail below.

The medical significance of this field of research was highlighted by the 2018 Nobel Prize in medicine, which was awarded to other researchers at other institutions, James Allison of MD Anderson Cancer Center and Tasuku Honjo of Kyoto University.

Allison and Honjo received the prize for their cancer therapies exploiting T cell regulating mechanisms intertwined with those that the Georgia Tech researchers study. Georgia Tech's Zhu and first authors Jinsung Hong and Chenghao Ge published their new research paper on November 12, 2018.

The research was funded by the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Institute of Neurological Disorders and Stroke. The agencies are part of the National Institutes of Health.

Under the microscope, tiny pipettes tug at living cells to exert forces on their structures, measure those forces and observe the consequences for the cells. Credit: Georgia Tech / Allison Carter.