MRC National Institute for Medical Research, London
Science for Health
IL7 - License to live: how training can improve your chances of survival
16 November 2011
An effective adaptive immune system depends on maintaining T lymphocytes at an optimal number and composition within the body. This is achieved by balancing production, cell division and survival of the constituent T cells. During their development in the thymus, T cells expressing randomly rearranged antigen receptor genes are auditioned in a process termed positive selection, such that only those cells with a functional T cell antigen receptor (TCR) survive. For successful candidate cells, continued life recirculating between the lymphoid tissues of the body depends on two key environmental signals. The first is interleukin-7 (IL-7) which is secreted within these lymphoid tissues and is vital for survival of T cells. The second comes from weak stimulation of the TCR that T cells receive when scanning antigen presenting cells that have no cognate antigen but only self antigens to present. T cells need these signals continuously to survive and if one or other of these signals is lost, T cells undergo rapid apoptosis. It seems intuitive that these two key signals must be functionally linked in some way to control T cell homeostasis. So far, there have not been clear answers to the questions of 'if' and 'how' this may be the case.
Charles Sinclair, working in the laboratory of Ben Seddon (pictured) in NIMR's Division of Immune Cell Biology, has been investigating whether there is any synergy or cross talk between the TCR and IL-7 signals that control T cell survival. By manipulating both the ligands that activate the TCR and the intracellular signalling activity downstream of the TCR, Charles asked if and when TCR signalling is required for the function of the IL-7 receptor. In fully developed T cells, signalling and function of both TCR and IL-7 receptors seems to occur completely independently of one another. In contrast, manipulating TCR signalling during T cell development in the thymus, revealed that the expression level of IL-7 receptor in fully developed T cells was dependent on those TCR signals received during positive selection. Survival of newly produced T cells was found to be critically dependent on the level of IL-7 receptor induced by the TCR signals during thymic selection.
Our research finally establishes a functional link between the TCR and IL-7 signals that regulate T cell homeostasis. Like many others, we expected active crosstalk between these signals in mature T cells but this seems not to be the case. What we did find, though, is that a mature T cell's ability to survive is not fixed, but is dependent on how well it did during thymic development. The amount of IL-7 receptor a mature T cell has is set during thymic selection, and this has a far reaching impact on that cell's long term survival. This kind of mechanism also suggests that the immune system 'thinks' the T cells that are best for immune response are the ones that audition most successfully during thymic development, as it has figured out a way to keep those cells around as long as possible. It will be interesting to see if this is true.
Ben Seddon
Original article
The long-term survival potential of mature T lymphocytes is programmed during development in the thymus
Charles Sinclair, Manoj Saini, Ina Schim van der Loeff, Shimon Sakaguchi, and Benedict Seddon (2011)
Science Signaling, 4(199):ra77. Publisher abstract.
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