Date Published: 29 July 2005

How do T-Cells recognise infected cells ? Oxford scientists explain.

A paper published in the journal Nature yesterday (28th July 2005) supports a theory about the way in which the human immune system identifies and responds to invasion. This describes research by scientists at Oxford University who show that a highly sensitive and specific immune response hinges on something as straightforward as large and small molecules jostling into size order.

T-cells (one of several types of lymphocytes, which are themselves a type of white blood cells) are a crucial part of our immune system: They patrol the body surveying cells and triggering the immune system to attack those that are infected.

The surface of every cell, including T-cells and infected cells, is covered in a variety of molecules. When a T-cell comes into contact with an infected cell, a receptor molecule on the T-cell’s surface will bind with a telltale molecule on the surface of the infected cell which flags up the infection (called a peptide MHC). This binding triggers the immune response.

The mechanism by which this triggering works has not been fully understood. However, it has been observed that T-cells are kept in check by a constant battle at their surface between the small molecules that trigger the immune response and large, long molecules such as CD45s which prevent the immune response from being switched on.

The CD45 plays a crucial role: the immune system can attack as well as protect the body, and allergies and serious autoimmune illnesses are the results of the immune system being activated inappropriately.

A crucial question is : "How do T-cells overcome the inhibitory effect of CD45s when they do need to launch an attack on invaders ?"

The answer is now shown to be the kinetic segregation model, conceived at Oxford 10 years ago by Professors Anton van der Merwe and Simon Davies, and confirmed in the recent paper published in Nature. Professor van der Merwe is an author of this paper, together with three other members of Oxford’s Sir William Dunn School of Pathology and a scientist at Imperial College London.

The model proposes that, because both T-cell receptors and the telltale peptide MHCs are relatively small molecules, they can only come into contact and bind when the bulkier CD45s are out of the way – in which case the immune response can be activated without impediment.

Molecules move around freely on the cell surface, and this constant reconfiguration means it is likely that groups of smaller molecules will spontaneously come together at some point. When these ‘clearings’ of shorter molecules occur on two adjacent cells, a ‘close contact zone’ between the two cells is formed, where the small molecules on each cell can come into direct contact with each other, rather than being held ‘at arm’s length’ by the presence of the larger molecules. The close proximity allows a T-cell receptor molecule to bind with any peptide MHC (that ‘flag’ for infection) that it finds. The bulky inhibitory molecules cannot enter the zone – which becomes fixed once the immune response begins – and so can no longer halt the immune response.

Researchers tested this theory by using long versions of the peptide MHCs. They found that these long peptide MHCs still bound to the T-cell receptors, but, as predicted, the immune response was not triggered.

David Wiseman from Oxford’s Sir William Dunn School of Pathology, one of the authors of the paper, said:

" By looking at the cells with an electron microscope we could actually see that the space between the cells was wider when we used the longer peptide MHCs. In that situation, the CD45s wanting to switch the immune response off were no longer being segregated out."

To check that the results were genuinely because of the size difference rather than any structural differences, the team did control experiments on completely different molecules with similar dimensions, proving that it was size that was important, not structure. The mechanism may well prove to apply not just to the immune system but to any system where cells meet and interact, which would encompass the nervous system and other crucial processes in the body.

The work was funded primarily by the Medical Research Council, while Dr Choudhuri was supported by the Wellcome Trust.

Source: Oxford University

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