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Department of Pathology

Project:The role of differentially spliced isoforms in regulating immune responses


Holmes ResearchThe immune system exists to defend us against infection. Part of that system works by having cells, known as lymphocytes, which carry highly specific receptors. Because of their specific nature there must be many different lymphocytes to cope with the many different infectious organisms which exist. This generates a problem for the immune system: how to ensure universal defence without risking autoreactivity or other damaging responses?

One of the ways in which lymphocytes cope with this problem is by having a very subtle system for sensing when to respond and what kind of response to make. The work of our group is focused on studying how lymphocytes control their sensing mechanisms, how they can regulate their activation thresholds. In particular we are interested in how the expression of multiple versions of proteins, (isoforms), generated by alternative mRNA splicing, can be used to modulate the function of specific proteins. We are working on two immune regulators which do this: CD45 and CTLA4, both have a powerful influence of immune responses but in very different ways. Our work has obvious potential applications in therapy where it would be advantageous to either boost or reduce the immune response, for example in cancer or autoimmune disease.


Key publications: 
  1. Jakubczik, F., Jones K., Nichols, J., Mansfield, W., Cooke, A. and Holmes N. (2016)  A SNP in the immunoregulatory molecule CTLA-4 controls mRNA splicing in vivo but does not alter diabetes susceptibility in the NOD mouse.  Diabetes 65:120-128.   doi:10.2337/db15-1175
  2. Salmond, R.J., McNeill, L., Holmes, N. and Alexander D.R. (2008) CD4+ T cell hyper- responsiveness in CD45 transgenic mice is independent of isoform. International Immunology 20:819-827.
  3. McNeill, L., Salmond, R.J., Cooper, J.C., Carret, C.K., Cassady-Cain, R.L., Roche-Molina, M., Tandon, P., Holmes, N. and Alexander D.R. (2007) The differential regulation by CD45 of Lck kinase phosphorylation sites is critical for TCR signaling responses. Immunity. 27: 425-437.
  4. Holmes N. (2008) A splicing switch for T cells. Science 321:646-647.
  5. Holmes N. (2005) CD45: All is not yet crystal clear. Immunology 117: 145-155.
  6. Ogilvy S., Louis-Dit-Sully C., Cooper J., Cassady R. L., Alexander D.R. and Holmes N. (2003) Either of the CD45RB and CD45RO isoforms are effective in restoring T cell, but not B cell, development and function in CD45-null mice. J. Immunol. 171: 1792-1800.
University Senior Lecturer
Division of Immunology

Contact Details

Department of Pathology
University of Cambridge
Tennis Court Road
+44 (0)1223 333871 / 33716
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