Immunity system complexity: T cells identify self, non- self (Introduction)

by David Turell , Tuesday, June 04, 2019, 20:36 (1998 days ago) @ David Turell

More on this T cell mechanism:

https://www.quantamagazine.org/immune-cells-measure-time-to-identify-foreign-proteins-2...

How these T-cells are able to make the distinction between self and non-self, between something that should be left alone and something that shouldn’t be, has been one of the central questions driving immunology research. (my bold)

"And strikingly, both teams got the same results: When a binding event lasted for more than around five seconds, the T-cell became active, but it failed to do so for anything less than that. “In some ways,” Groves said, “the whole T-cell receptor signaling network is like a little chemical computer that’s measuring binding times, and it’s also a single-molecule sensor on top of all this.” (my bold)

"This process works because the immune system undergoes a sort of training period during its early development: Nascent T-cells are presented with all the self molecules in the body, and cells that bind for more than five seconds to anything get weeded out. That way, the T-cells left to make up the body’s immune system are those that bind for a long time only with things they’ve never seen before.

"How the cells measure the length of a binding event is still unknown, but experts have sketched out an idea of what most likely happens: From the moment a T-cell receptor binds to a molecule, a number of irreversible biochemical steps have to take place before the cell will activate. If the molecule detaches too early during this signaling cascade, everything has to start over from step one. Researchers, including Weiner, Schamel and Groves, are still trying to figure out what those intermediate steps are, and how each of those steps contributes to the T-cell’s ability to keep track of binding time. (my bold)

"But Tischer and Weiner’s simplified T-cell experiment provided a preliminary, and surprising, hint: The clock doesn’t seem to start immediately after the target molecule binds to the T-cell receptor; rather, there is some kind of undetermined hiatus.

"This still needs to be confirmed in a natural T-cell system, and some researchers have their doubts (Groves, for one, thinks that multiple levels of the signaling cascade track the binding time, and that the receptor contributes to that). Still, if true, “it would be very strange,” said Schamel, who is also not yet fully convinced. “It’s a very puzzling and unexpected result, because you would have always thought that time would start counting with the first event, when the [molecule] binds. But no, time seems to start counting later.”

"Weiner added, “The step we thought was the most likely [for kinetic proofreading] appears not to be the critical one.” Rather, steps that take place further down the line, and that are less directly connected to what’s going on at the binding site, seem to be involved. To him this indicates that “discriminating self from non-self is a property of the more extended signaling network … and [raises] the very interesting question of exactly what the receptor is contributing to this process."

Comment: Note my bolds. A very complex automatic arrangement. The T cells go through an important learning process. A system that must be designed to fill these requirements. Not by chance.