Mechanism for CD8+ T cell recognition and removal of senescent tissue cells during ageing

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The prevailing view is that the repeated stimulation of the immune system by microbes throughout life exhausts and ages particular types of white blood cells. This may be why immunity decreases during ageing. It was therefore surprising to note that instead of being decrepit, these old cells actually become very good at responding to infections in a promiscuous fashion and not by using their usually very specific microbe recognition apparatus. Therefore, during ageing, white blood cells adapt to respond more broadly to microbes rather than lose their function totally. Our preliminary experiments identify a group of proteins known as sestrins that regulate this exchange of functions. We will first explore the roles of the sestrins further, to understand the breadth of functional changes in human white blood cells that they can regulate. We will also complement these studies by studying white blood cells for old genetically altered mice that do not express the sestrins. The accumulation of old tissue during ageing reduces organ function. Exciting new studies in the mouse have shown that the removal of these old tissue cells improves the function of many different organs and the mouse behaves more like a young animal. Therefore, the removal of old immune cells in tissues may be a strategy for rejuvenation of organ function leading to increased well-being during ageing. White blood cells can directly recognize and eliminate old cells in tissues and exploiting this interaction may improve age-associated organ dysfunction. White blood cells that have more promiscuous immune activity in older people can also recognise and clear old tissue cells. Therefore, the sestrins, that regulate the acquisition of this activity, may be indirectly involved in the removal of old cells in the body. We will explore further the interactions between white blood cells and old tissue cells to identify new ways by which they may interact together. One unanswered question is why do old tissue cells accumulate in organs of aged people if the immune system can recognize and clear them? We think that old tissue cells can hide from white blood cells that are looking to kill them. This evasion strategy involves the induction of inhibitory receptors on the senescent cells in organs. We have identified one such inhibitory receptor, HLA-E and we will now investigate if others are also involved. Understanding the nature of this evasion mechanism could lead to the identification of new ways to enable the immune system to work more efficiently to clear senescent cells and improve organ function in older humans that would lead to an increase in health and well-being.The final question is whether interactions between white blood cells and old tissue cells happen in real life and not just in a test tube. We have developed methods for investigating immunity in human skin. We take small skin samples from young and old individuals and look at the multiple different populations of immune and non-immune cells in the same tissue sample. We will also inject the skin with an immune stimulus and investigate the multitude of interactions between different cell types at different times after the initiation of the immune response. We will identify the different types of interaction between immune cell and senescent tissue cells in the skin of young and old subjects. This will provide a roadmap to how sestrins and NK receptors develop on T cells during an immune response and potentially identify which cellular interactions in the skin can be targeted to boost immunity during ageing.