Project F: Immune Regulation and Ageing

Department of
Coordinators: BJ Kroesen, E Brouwer, A Boots

Age-associated alterations of the immune response (immunosenescence) have a strong clinical impact and contribute to autoimmune morbidity (frailty) and mortality in the elderly. Immunosenescence is characterized by i) thymic involution leading to a steady decline in the production of naïve T cells, ii) shrinkage of the T cell repertoire through continuous antigen stimulation favoring the development of functionally altered, oligoclonal, senescent T cells (identified by CD28 loss and telomere shortening) and iii) a chronic low degree of inflammation (termed inflamm-aging) as evidenced by increased serum levels of inflammatory cytokines and acute phase proteins.

It is currently not known how aging affects the prevalence and functionality of different immune cell subsets. The altered cytokine milieu as a consequence of inflamm-aging may 1/ accelerate replicative senescence in T cells and 2/ favour a shift (away) from the Treg effector arm of the immune system towards the pro-inflammatory Th17 effector subset associated with tissue pathology. Both processes may contribute to the decline in peripheral T cell numbers and the development of an immune risk phenotype. In addition, other immune cell subsets, such as antigen presenting cells and NK/T cells, may be affected and involved in the process of immunosenescence.

Project 1
Senescent T cells are thought to contribute to co-morbidities in the auto-immune prone elderly. The molecular mechanisms determining/regulating the functional consequences of T cell replicative senescence will be studied using the UMCG microRNA platform.
In addition, an assay will be set-up for functional rescue of exhausted T cells (revival of tired T cells). In this assay the role of identified microRNAs or other reagents may be studied.

Project 2
Treg function in the elderly is a relatively unexplored field. Earlier studies have shown that pro-inflammatory stimuli, such as observed during inflamm-aging influence a Treg to Th17 shift, a process that can be inhibited by HDAC inhibitors. The project aims to describe Treg function in the elderly and to establish the molecular mechanisms regulating Treg stability and/or plasticity. The ultimate aim is to manipulate factors modulating or preserving Treg function.

Project 3
Elderly with impaired immune function can be identified based on measurements in peripheral blood (immune risk phenotype). PBMC from elderly with and without an immune risk phenotype will be studied for their ability to respond to specified microbes (microbe associated molecular pattern recognition) or specified endogenous danger signals (danger associated molecular pattern recognition) in order to establish the role of the innate immune response in the immune compromised elderly.

Project 4
iNKT-cells are a subset of T-lymphocytes that share properties of Natural Killer cells and conventional T-cells. Like T-cells, iNKT-cells arise from thymocyte precursor cells. The rapid response of iNKT-cells, which is indicative of an innate immune response, rather than an adaptive immune response, may allow iNKT-cells to regulate adaptive immunity. As such, iNKT-cells function at the interface of innate and adaptive immunity, regulating immune tolerance and providing protection against viral and bacterial infections and autoimmune inflammation. iNK/T-cells from young versus elderly subjects will be studied for their immune regulatory characteristics.