Reversing senescence and exhaustion signalling pathways in primary human T lymphocytes during ageing

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The potency of the immune system should not be undrestimated. Without effective immunity our bodies would turn into rotting carcasses within a few days. However, such a potent defense against invading microorganisms has to be effectively controlled as there would be dire consequences if our immune systems turns against ourselves. There are two processes that control immunity the first is a process called exhaustion, where the over activation of white blood cells known as T lymphocytes leads to loss of their functional activity. This is achieved through binding of surface proteins on the T cell surface that inhibit the production of toxins that kill microorganisms properly and also prevent their proliferation. Exhaustion is therefore regulated by the signalling through cell surface inhibitory receptors. Secondly, the repeated stimulation of T lymphocytes leads to the loss of their replicative capacity and this is due to the loss of specialized structures at the end of chromosomes that are made of DNA and are known as telomeres. Excessive loss of telomeres initiates signalling pathways that sense DNA damage that turn off the capacity of the cell to proliferate. This process is known as senescence and unlike exhaustion, is initiated by signals from damaged DNA in the nucleus.As we get older (>70 years), we become more susceptible to infections, even those to which we were immune in our youth. This indicates that the immune system becomes too fragile to be fully effective in preventing the lifelong assault on our bodies by micro-organisms. However the reasons why the T lymphocytes (white cells) isolated from old individuals are dysfunctional is not known. It is well recognized that the T lymphocytes from older humans have characteristics of senescent cells however it is not know if they may also be exhausted. We have recently found that in young individuals (<40 years), we can block proteins in the cell that regulate senescence or proteins on the cell surface that regulate exhaustion to increase their function. The key question is whether we can boost the function of T lymphocytes from older humans by blocking senescence pathways, exhaustion pathways or both. This is an important goal given the demographic shift of humans towards an older age with defective immunity that leads to increases of infection and malignancy. The main aims therefore are:1) To investigate the expression of senescence and exhaustion control elements in the T lymphocytes of older humans.2) To determine whether active mediators called cytokines that are increased in the blood of older humans can turn on senescence or exhaustion pathways.3) To investigate if we can block senescence or exhaustion in T cells from older humans using specific inhibitors to boost their function and capacity to proliferate (we have shown recently that this can be done in young subjects).4) To investigate whether blocking senescence or exhaustion signalling can increase the functional activity of T cells of older humans that are specific for cytomegalovirus, that appear senescent, or varicella zoster virus that causes shingles, the incidence of which is increased in older humans.All this work will be performed on leucocytes that are obtained directly from the blood of older humans and therefore has directly relevance for the ability to boost the defective immunity that occurs during ageing in humans.