The integration of human T cell senescence and function at the molecular level

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Immunity decreases during ageing, resulting in the increased susceptibility of older individuals to both infections and cancer. The powerhouse of immunity is the T lymphocyte, that recognizes and combats malignant and infected cells. However these cells have to expand in number, akin to the mobilization of an army, to combat the infectious or cancerous challenge. This mobilization takes time and during this lag period, protection is offered by another population of leukocytes in the front line known as natural killer (NK) cells, that are less specialized in the recognition of the invaders but highly efficient in killing them. Efficient immunity therefore, requires that the 'beserker' NK cells that are involved in the first line of defense and the specialized T cells that are mobilized later fulfill their role at different phases of the war. In earlier studies we showed that T cells get older progressively as a result of repeated immune challenges and in older humans, immune protection is mediated by the equivalent of "Dad's Army" soldiers that do not function as well as younger leukocytes. The changes in old T lymphocyte population includes the decrease in their ability to proliferate and increase in numbers after immune activation, this expansion is essential for increasing the number of T cells that can seek and destroy the invaders. We showed that the decreased activity in old T cells was due to an active signaling process mediated by p38 MAPkinase and that by blocking the activity of this molecule, we could enhance proliferative activity. p38 is one of a family of distinct MAP kinases, others include JNK. Our preliminary results indicate that the T cells in old individuals also express JNK spontaneously, without the requirement of any additional activation and that these molecules may also regulate the function of T cells. Thus while we showed that p38 was a brake on lymphocyte function, our recent preliminary observations show that JNK is an additional brake, that may be engaged simultaneously. Both brakes work to inhibit different processes. Furthermore, both brakes are engaged by the energy sensor molecule AMPK that is activated by low nutrient availability or the process of ageing in the cells. We will investigate whether blocking JNK, using novel reagents that we have developed in the laboratory can restore additional functions to those that are regulated by p38 in these old T cells. Furthermore, we will determine whether either or both p38 and/or JNK MAP kinases regulate the NK-like function of old T cells. Another novel part of this investigation is the use of a human experimental system where we induce and antigen specific response by injecting chickenpox virus proteins into the skin to induce a memory immune response that we can harvest cells from. This is a totally unique model that has been developed and refined in the Akbar lab over 18 years. All the appropriate safety and ethical approvals are in place to do this. This will enable the study of how quickly leukocytes age in the skin during an immune response and the role of AMPK and the MAP kinases in this process. We will also be able to determine when T cells start to develop NK characteristics in real life, after immune stimulation in vivo.These studies will identify changes that occur in the early and late phases of the immune response and how ageing affects this. More importantly, we will determine whether it is possible to enhance the activity of old T cells by removing the MAP kinase brakes that will provide proof of principle of whether we can enhance the activity of these cells during ageing.