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
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
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
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
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
Sir William Dunn School of Pathology and a scientist at Imperial College
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
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
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