Immunity: feedback loop perfects thymocytes (Introduction)

by David Turell , Monday, November 12, 2018, 20:00 (1989 days ago) @ David Turell

Precise controls of thymocytes makes sure they do not attack normal tissue:

https://medicalxpress.com/news/2018-11-suicide-handshakes-precursor-cells-pose.html

"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 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.

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"'Before our work, force was not considered as a factor in thymocyte selection and now it is."

"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.

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"Like blood cells, human thymocytes are born in bone marrow, but they travel to the thymus, a small organ just below the neck, where they run a gauntlet of selection tests. Failing any one selection means death by cell suicide; passing all selections promotes thymocytes to T cells that depart the thymus to battle our bodies' foes.

"One selection checks T cell receptors (TCR), which are on the thymocyte's membrane, to ensure they are properly formed then to see if they recognize self-antigens, i.e. molecules that identify the body's own cells. Then another selection, called negative selection, tests TCRs to make sure they don't react too aggressively to self-antigens.

"Cells that pass these checks then have TCRs that tolerate self- yet react to enemy antigens.
"You don't want the cells with strongly grabbing receptor sites to turn against the body itself," said Zhu, whose study focused on negative selection.

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"For about two weeks in the thymus, multiple T cell receptor sites engage in one- or two-handed handshakes, which send signals into the thymocyte that make it either mature into a T cell or commit suicide.

"The researchers found that the two-handedness markedly resisted the force applied to break the grip between the T cell receptor and the self-antigen, thus prolonging the duration of the handshake. A long grip sent signals for the thymocyte to die.

"That's the study's elegant finding," Zhu said. "That the force is significant for the selection to work."

"The researchers also made the novel discovery that CD8's handshake participation constitutes a signal coming from inside the thymocyte back out to the self-antigen in answer to its initial signal.

"Together, the outside-in and inside-out signals create a feedback loop that perpetuates the handshake:

1. Self-antigen touches receptor.
2. Receptor fires signal into cell and interacts with self-antigen too aggressively.
3. Inside cell membrane, signal pulls CD8 closer.
4. Outside cell membrane, CD8 strengthens handshake.
5. When the self-antigen slips a bit, the double-handed grip can coax it back into the receptor, kicking off another signal, restarting the signaling cycle again and again.
6. Many feedback loops trigger cell suicide."

Comment: Au automatic system controlled by a feedback loop. All life maintains its homeostasis by these loops. This is an excellent example. Too complex for chance, it had to be designed.