Highlight Publication November 2007

Louise McNeill, Robert J. Salmond, Joanne C. Cooper, Céline K. Carret, Robin L. Cassady-Cain, Marta Roche-Molina, Panna Tandon, Nick Holmes, and Denis R. Alexander
The Differential Regulation of Lck Kinase Phosphorylation Sites by CD45 Is Critical for T Cell Receptor Signaling Responses
Immunity 27: 425-437, 2007
doi:10.1016/j.immuni.2007.07.015 

This publication is discussed in a Preview on page 421 of the same issue of Immunity:
Why Is There so Much CD45 on T Cells?
Rose Zamoyska
doi:10.1016/j.immuni.2007.08.009 

Lay Description

Everyone knows that sometimes their bodies fight off bugs efficiently whereas at other times they seem to succumb very easily. There are many different reasons for this, but it’s a reminder that our immune systems, which defend us against attack by bacteria and viruses, can operate at different efficiency thresholds

T cells are the white cells that specialise in defending the body against infection by viruses, and their responses also vary depending on different internal mechanisms in the cells themselves. If the T cell responsiveness is low, then we don’t fight off viral infections very efficiently, but if their responsiveness is too high, then T cells end up attacking our own tissues and cause diseases such as diabetes. So getting the balance just right is really important.

This paper in Immunity sheds new light on how T cell responses are regulated, in particular by a molecular ‘gate-keeper’ called CD45. T cells recognise infection of cells by the infected cell waving a ‘molecular flag’ containing a small piece of the virus itself. This acts as a warning sign recognised in turn by T cells which proceed to wipe out the infection. The recognition process is carried out by a receptor on the T cell surface known as the T cell antigen receptor. The CD45 gate-keeper controls the strength of the activating signals transmitted to the T cells through this receptor.

The paper shows that CD45 acts like a rheostat to either increase or decrease the threshold of signalling through this receptor. Amazingly, it turns out that only 3% of the normal activity of CD45 is sufficient to make the receptor function, albeit not that efficiently. At intermediate levels of CD45 the receptor threshold becomes quite low and the T cell responses become correspondingly much higher than usual. As the CD45 level moves up to normal levels, the T cell responses are damped down again, to achieve the ‘Goldilocks level’ at which the responses are ‘just right’.

The paper also describes the detailed molecular mechanisms whereby CD45 carries out its gate-keeper role in relation to the T cell antigen receptor, showing that it would be quite a difficult pharmaceutical target if one wanted to suppress the actions of T cells. Unless the inhibition of CD45 was nearly complete, there would be a danger of inappropriately activating the T cells, exactly the opposite of the desired effect.

Ever since CD45 was first clearly identified back in the 1980s, immunologists have been mystified by the huge abundance of CD45 on the T cell surface. Why have so much when a little would apparently do the gate-keeper trick? It turns out that you need only a little CD45 to make the T cell antigen receptor function, but you need a huge amount to damp down the receptor so that the T cells don‘t get too active and start attacking the body’s own tissues. Millions of years of evolution have honed the CD45 level to the point at which T cell responses are just right, for most people most of the time, and for that we can be thankful.

About the Joint Lead Authors

Louise McNeill joined the Denis Alexander lab in 2001 to take on a dual role as researcher and Laboratory Manager, having previously completed a PhD at MRC NIMR, Mill Hill. During her 5 years at the Institute, Dr McNeill worked for 50% of her time on the role of CD45 in T cells. In 2006 she left Babraham to take up a new research position, working with Professor Hill Gaston, Professor of Rheumatology in the Medical School at Cambridge University.  

Robert Salmond came to the Institute in 2001, also to take up his first postdoc position immediately after finishing his PhD in Bristol, and prior to that a  degree in genetics from Edinburgh. His first project was on a tyrosine phosphatase called SHP-2, so it was a natural transition to work on CD45, another tyrosine phosphatase, when a second postdoc position came along in Denis Alexander’s laboratory.  Dr Salmond left Babraham in 2006 to take up a research position in a related field at MRC NIMR, Mill Hill.