Lymphocyte development & homeostasis.

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The intrinsic lifespan of lymphocyte subsets increases as the cells progress through the immature, naïve and memory stages. This represents a paradigm for the reprogramming of cell lifespan in vivo but the molecular basis for this is incompletely understood. For example, while naïve B and T cells may survive for months, memory B and T cells last for years, perhaps reflecting a greater potential for self-renewal [49]. Maintenance within the naïve pool is also dependent upon interclonal competition and memory cells are far less subject to this competition which may also contribute to their increased lifespan. The size of the pool of naive lymphocytes is limited by competition for trophic factors such as the TNF superfamily member BAFF (tnfsf13B) in the case of Marginal Zone (MZ) and Follicular (B2) B cell subsets and IL-7 in the case of T cells [50]. B1 B cells, by contrast, maintain self-renewal independently of BAFF and the factors that regulate the lifespan of certain epithelial T cell subsets remain unknown. These features of lymphocyte lifespan are linked to the extrinsic and intrinsic factors that dictate the upper limits of the number of lymphocytes at each developmental stage. This may be linked to specific signalling pathways that regulate organ size, e.g. the PI3K pathway. For instance, the number of marginal zone B cells is proportional to the activity of the PI3K pathway within B cells. The PI3K pathway in T cells determines the number of T-follicular helper cells and, in a non-cell autonomous manner, the number of germinal centre (GC) B cells. Our identification of genes and pathways that regulate lymphocyte development and survival now permits us to investigate mechanisms through which these pathways function and connect to other components of lymphocyte homeostasis (e.g. the Bcl2 pathway). In addition, we have found that TIS11b is necessary for the development and turnover of the B1 and MZ B cell pools. This finding not only confirms the need to uncover how signalling pathways regulate the transcriptional programmes affecting cell fate but also emphasise the profound effects that the control of mRNA stability and translational efficiency can impart. So far, three out of the 8 mouse GIMAP GTPases have been shown to influence lymphocyte survival, either positively (GIMAPs 1 and 5) or negatively (GIMAP4 – an accelerator of apoptosis) [7, 51-52]. Given their strong expression in resting lymphocytes, roles can be expected for the remaining family members shared across species, namely the cytosolic members GIMAP6, 8 and 7/9. We predict that, in common with most GTPases, the cell biological role of the GIMAPs will lie in the re-fashioning of parts of the lymphocytes’ intracellular membraneous organelles in response to developmental, homeostatic and activation requirements.

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