The concept of space and competition in immune regulation.

Abstract

Regulation of cell numbers and organ size in multicellular organisms is an important principle in biology. Experimental data in developmental biology indicate that there are mechanisms by which organs sense their total mass, linked to the regulation of cell size and proliferation, but not solely determined by either.1,2 Active monitoring of organ size is suggested by regeneration experiments following removal of part of an organ; this has been best illustrated by the regeneration of mammalian liver after partial hepatectomy.3 Another example is the demonstration that, following transplantation of multiple spleen fragments, the total spleen graft mass tends to reach a plateau which is in the range of variation of normal spleen weights.4 There are a multitude of mechanisms that regulate the number of cells (reviewed in ref. 1). For instance, the number of cell divisions may be predetermined, as in the nematode Caenorhabditis elegans,5 or divisions may stop after a given time interval (a mechanism for cell number control used in cardiac myocytes). Furthermore, hormones and components of signal-transduction pathways regulate growth and cell division, e.g. growth hormone6 and components of the insulin-signalling pathway.7 Another widely used principle in biological systems is competition for limiting resources, such as secretory molecules or cell-contact mechanisms. This is evident, for instance, in the control of oligodendrocyte precursors, which are regulated via the concentration of platelet-derived growth factor, whereas the number of mature oligodendrocytes is related to axon-dependent survival signals that are limited in amount and assure that the final number of oligodendrocytes is matched to the number of axons.8–10 In the mammalian immune system, size control checks maintain the number of peripheral T cells at more or less constant levels. This is not the result of a finite capacity for cell division, as it has been shown that T cells, following serial transfer into irradiated hosts, are able to divide up to 56 times in vivo, an expansion potential similar to that of colony-forming units.11 Thus, alternative mechanisms are involved in controlling the numbers of T cells in the face of ongoing new production from the thymus (at least for a certain period in development) and continuous expansion in response to antigenic stimuli. The American physiologist, Walter Cannon, introduced the term ‘homeostasis’ to describe the tendency of an organism to restore its original status in the face of unexpected disturbances.12 Permutations of this term are now widely used by immunologists referring to various response modes of T cells when the equilibrium is disturbed. The intrinsic dynamics of the immune system pose constant challenges threatening the equilibrium, and it is therefore understandable that the immune system has developed several layers of homeostatic control mechanisms.