Research
My research interests are in the area of the early events occurring after lymphocyte activation. CD45 is a transmembrane protein tyrosine phosphatase which is expressed on the surface of nucleated cells of the haemopoietic system. My group generated a null-phenotype "knockout" mouse for the CD45 gene. We have used this model to study the role of CD45 in development and regulation of lymphocyte activation. Our in vivo genetic complementation approach has led to two major conclusions. First, that CD45 is a non-linear dose-dependent regulator of Src family kinase, and consequently T cell, function with an optimum level of about 0.25x wild-type. Second, despite the general expectation, that the well-conserved protein isoforms do not differ sufficiently in function for this to be apparent even in our quantitatively sensitive in vivo system. I am continuing to pursue research into CD45 and in particular am trying to understand how the activity of CD45 is regulated.
Publications
Miyadera K, Kato K, Aguirre-Hernández J, Tokuriki T, Morimoto K, Busse C, Barnett K, Holmes N, Ogawa H, Sasaki N, Mellersh CS, Sargan DR Phenotypic variation and genotype-phenotype discordance in canine cone-rod dystrophy with an RPGRIP1 mutation. Mol Vis. 2009 Nov 11;15:2287-305.
Holmes N. A splicing switch for T cells. Science 2008 321:646-647.
McNeill L, Salmond RJ, Cooper, J.C., Carret, C.K., Cassady-Cain, R.L., Roche-Molina, M., Tandon, P., Holmes, N. and Alexander D.R. The differential regulation by CD45 of Lck kinase phosphorylation sites is critical for TCR signaling responses. Immunity 2007. 27: 425-437.
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.
Lopez, M. C. and Holmes N. (2005) Phenotypical and functional alterations in the mucosal immune system of CD45 exon 9 KO mice. International Immunology 17: 15-25.
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Holmes N. CD45: All is not yet crystal clear. Immunology 2005 117: 145-155.
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.
