Title: Beta-adrenergic regulation of the aged immune system
Funder: Dunhill Medical Trust

Abstract: The overarching aim of the current proposal is to determine whether inhibition of cell immunity by β-adrenergic stimuli is increased with age and thereby provide innovation in therapeutics to improve immune function and health in the ageing population. Adrenaline and noradrenaline are released during sympathetic nervous system activity and directly regulate immune function by engaging β2-adrenergic receptors (β2AR) that are expressed by leukocytes. In general, this adrenergic regulation causes suppression of immune function. Clinical implications include increased susceptibility to infections, reduced cancer-specific T cell effector functions and cancer progression, and diminished responses to immunotherapies including vaccination. The suppression of T cell function following βAR stimulation is very similar to the loss of immune function observed in the aged T cell compartment, namely reduced proliferative and functional (e.g., cytotoxic potential and IFNy production) responses. Importantly, the PI and others has shown that β2AR expression upon T cells is increased with cell differentiation meaning that the cells that accumulate during immune ageing are sensitive to β-adrenergic stimulation. This observed similarity between the effects of βAR immune regulation and the loss of immune function in older adults, combined with the fact that β2AR expression upon T cells is increased upon highly differentiated T cells that accumulate with age supports the main hypothesis of this proposal; that enhanced β2AR responsiveness of the aged T cell compartment will result in increased inhibition of T cell function in old individuals. The PI’s lab group have shown that differentiated T cells are highly responsive to β2AR stimulation resulting in increased classical βAR-signalling (PKA activity), activation of the senescence-associated p38 signalling pathway, increased cellular ROS levels, and a greater inhibition of cellular functions, such as cytokine production. It is not known whether this increased βAR-regulation of differentiated T cells results in greater immunosuppression of the aged immune system. Answering this fundamental question is the main aim of the current proposal. The primary objectives of the project are therefore too: 1. Determine the level of β2AR expression upon T cells and the wider PBMC population obtained from young and old participants. 2. Compare the impact of βAR stimulation on cell function in PBMCs obtained from young and old participants. Methodology A cross-sectional study design will be used to determine the difference in β2AR responsiveness between young (<​35 years) and old (>65 years) healthy human participants. βAR responses will be manipulated via the use of a βAR-agonist and β2AR-specific antagonist with or without subsequent T cell receptor activation. Assessment of βAR-signalling and cellular functional responses will be achieved by mass-cytometry using full fluorescent spectrum technology provided by a Cytek Aurora. βAR suppression of the immune system extends into other lymphocytes and myeloid cells. Therefore, a secondary aim of this proposal is to assess the β2AR responsiveness of all monocytes, DCs, NK cells and B cells found within the peripheral blood. The use of the Cytek Aurora will facilitates simultaneous analysis of complexed cell samples, cell signalling and functional characteristics. The data generated will provide previously unavailable evaluation of the βAR regulation of the complexed immune compartment and how it is altered by age. Deliverable impact This work will determine whether there is increased βAR regulation of the old immune system. This data is critical to support larger grant funding opportunities to assess βAR-regulation of immunity across the life course. This will include using both in-vitro and in-vivo βAR stimulation protocols such as utilising psychological stress to induce sympathetic nervous system activity with and without beta-blockers, or direct infusion of βAR-agonist. The future ambition is to manipulate βAR signalling, during antigen challenge e.g. skin test challenge. The grand promise of this body of work is providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents e.g. during vaccination of the older population. The immediate impact of this work will be the training of at least two students in immunological and ageing research. Importantly, it will support an early career PI to strengthen her research esteem and establish an independent research group by supporting the development of an innovative and original research idea that will advance a larger competitive research proposal.

Lay abstract: Normal immune function is vital for good health. The correct balance between immune activation, for protection against cancers and infections, and immune restraint, to prevent inflammation, is essential to our wellbeing. Immune balance is maintained by communication between the nervous, endocrine (hormonal) and immune system. The sympathetic nervous system regulates immune function by releasing the stress hormone adrenaline. Adrenaline decreases our immune protection to infections and cancers and may reduce the effectiveness of vaccinations. The aim of this work is to see how adrenaline alter immune cell function. Importantly, this work will find out whether the aged immune system is more vulnerable to adrenaline regulation. The results will help us understand how the release of adrenaline that fluctuates daily, and is seen in psychological stress, anxiety, sleep disruption, and is altered during ageing, may reduce immunity. Alterations to how our immune cells respond to adrenaline will change the way the immune system works. Over time our immune cells increase the number of adrenergic receptors present upon the surface of the cell. This means that the cells become sensitive to adrenaline, and this could result in altered cell function. We have found that this increase in adrenergic receptors does results in increased sensitivity of immune cells to adrenaline, and that this causes a loss of normal immune responses. As the number of adrenergic receptors increases upon our immune cells over time, we predict that immune cells from old individuals will be more sensitive to adrenaline than immune cells of young people. If this is proved to be true, then adrenaline may cause a further reduction in immune protection in old people. The main aim of this work is to find out whether the aged immune system is more sensitive to adrenaline when compared to the young. We will use a technique that allow us to study the many different types of immune cells found in the circulating blood. We will obtain blood from young (<​35 years) and old (>65 years) individuals and examine how cells respond to adrenaline in the laboratory by changing how they function e.g., changes to the cells ability to divide into two. The results of this work may provide evidence that adrenaline can reduce immunity in old adults. This means that drugs which prevent the actions of adrenaline (e.g. β-blockers) may be used to promote immune responses in old people, such as when receiving a vaccine.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM