Abstract

In a healthy individual numerous homeostatic mechanisms contribute to the overall stability of the mature pools of T and B lymphocytes present. For instance, the generation of new cells from haematopoietic precursors in the bone marrow and thymus is kept in balance with the loss of mature cells from peripheral compartments of the body; in another example, the proliferation of specific clones of T or B cells in response to an antigen or an infection is followed by a phase of clonal contraction which returns the repertoire close to its starting state. The importance of homeostasis is evident from several immune diseases associated with having too few lymphocytes (lymphopenias) or too many (e.g. lymphadenopathies). The regulation of lymphocyte survival vs. programmed cell death (apoptosis) is therefore essential to the survival of the healthy organism.

Geoff Butcher’s group is studying a family of cell signalling molecules which appears to play a part in the maintenance of lymphocyte populations. This is the GIMAP family (GTPase of immunity associated proteins) made up of 7-8 putative guanine nucleotide hydrolases (GTPases) encoded in mammals in a gene cluster on a single autosome (chromosome 7 in humans). Attention was drawn to this family in 2002 when a mutation in one of its members, GIMAP5 , was shown to be the basis of severe peripheral lymphopenia seen in the BBDP rat model of spontaneous autoimmune type 1 diabetes mellitus. This lymphopenic phenotype suggested that GIMAP5 is an anti-apoptotic regulator of normal T lymphocyte survival. At this stage, however, little was known about this enigmatic family of GTPases and so Butcher’s group has undertaken characterising it in greater detail and searching for insights into its functional roles and mechanism of action.