The way immune cells pick friends from foes can be described by a classic maths puzzle known as the “narrow escape problem”.
That’s a key finding from a new paper led by RDM researchers, published in the journal Proceedings of the National Academy of Sciences. The study, whose first author is Dr Ricardo Fernandes, a former student of the Davis lab (now at Stanford University), was the result of a close collaboration between biologists, immunologists and mathematicians at the Universities of Oxford and Cambridge in the UK, the University of British Columbia in British Canada, and the University of Skövde in Sweden.
The narrow escape problem is a framework often applied in cellular biology. It considers the situation of randomly moving particles trapped in a space with only a tiny exit, and calculates the average time required for each one to escape.
“This is a new application for some familiar equations,” says co-author Justin Tzou, now at Macquarie University’s Department of Mathematics and Statistics.
The researchers analysed how potential pathogens are probed by T cells, which identify and attack invaders. The researchers discovered that the equations used in the narrow escape problem offer a good explanation for whether an immune response is triggered or not.
“The narrow escape problem turns out to be a close cousin of the situation with T cell receptors,” Justin says. “It is about determining how long a diffusing particle remains in a certain region before escaping.”
The unique shape of T cells creates what has been termed a “close-contact zone” for triggering molecules called T cell receptors. Unlike most cells, which have relatively smooth surfaces, T cells are covered in ruffles, bumps and other protrusions.
Scientists have known for a long time that T cell receptor molecules sit on the surface of the cells to recognise enemies and trigger a hostile response.
The receptors contain molecular patterns that mirror those found on the surfaces of bacteria, tumours, and other dangerous interlopers. But exactly how the process of recognition and triggering works – and particularly how it works so quickly and accurately – has been a mystery.
The researchers believe the unusually lumpy shape of the T cell plays a vital role. The protrusions on the surface mean that its area of contact with a potential enemy cell is very small – only a couple of hundred nanometres across, or a thousand times smaller than the width of a human hair.
And the size of the contact turns out to be key. “It’s very important that the contact is not too large, so that the T cell receptor can report the presence of the invader, or it can escape very quickly”, says Professor Simon Davis, one of the senior authors of the study. “If the receptor was to linger too long in a large contact, the T cell would start to attack us.”
We think this is the first case in which the shape of a cell seems to inform its decision-making.
- Professor Simon Davis
The researchers hope their work will provide new insights into immune deficiencies and auto-immune conditions, in which the immune system turns against the body’s own cells.