Geoff Butcher

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Unusual GTPases implicated in lymphocyte development and survival

In a healthy individual it is critically important that the number of mature T and B lymphocytes is maintained at a steady level. This process is termed lymphocyte homeostasis. The generation of new lymphocytes from precursor cells in the bone marrow and thymus is balanced by the loss of mature cells from peripheral compartments of the body.

Sometimes numbers of lymphocytes can increase dramatically, for example during infections. Once the infection has been successfully defeated by an immune response, lymphocyte numbers return to a normal level. Numerous homeostatic mechanisms contribute to the overall stability of the mature lymphocyte pools: the importance of this 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. Significant efforts are underway, worldwide, to gain knowledge of the genes and proteins involved in the control of this process.

We are studying a family of cell signalling molecules which may play a part in the maintenance of lymphocyte populations. These are the GIMAPs (GTPases of the immunity associated protein family) which, in mammals, comprise 7-8 putative guanine nucleotide hydrolases (GTPases) encoded in a gene cluster on a single autosome (chromosome 7 in humans). Particular attention was attracted to this family in 2002 when a recessive mutation in one of its members, GIMAP5, was shown to be the basis of severe peripheral lymphopenia in the BB strain of rats that develops autoimmune diabetes mellitus spontaneously.

This suggested that GIMAP5 is an anti-apoptotic regulator of normal T lymphocyte survival and this idea has been supported by experiments in mice and in human lymphoid cell lines. Meanwhile, work on a different GIMAP protein, namely GIMAP4, suggested that this family member, by contrast, accelerates apoptosis. Such a process may be advantageous after acute expansions of lymphocyte numbers in response to infections, in order to return the lymphocyte pool to its normal state as rapidly as possible.