Major achievements

The group has specialized in studying the restructuring of the CD8 T cell repertoire in healthy elderly persons and, hereby, has made a number of important discoveries.

Thus it has shown that the CD8+ naive T cell population is not only extremely small, but has also impaired homing receptors, a restricted diversity and shortened telomeres in comparison to young controls. Naive T cells are therefore unlikely to guarantee full immunological protection following exposure to neo antigens in elderly persons.

We have also shown that a lack of fully functioning naive T cells can, at least partly, be compensated by an increasing number of memory T cells, in particular, a subset within this population that expresses CD25 constitutively without being regulatory. This population which only occurs in elderly persons who still have a good humoral immune response, is diverse, produces substantial amounts of IL-2 and also IL-4 and has a good proliferative potential as indicated by its long telomeres.

Additionally we could demonstrate that elderly persons who no longer have an intact immune response and do not have CD8+CD25+ memory T cells have a dominance of CD28- effector cells which produce large amounts of pro-inflammatory cytokines and are frequently specific for the Cytomegalovirus (CMV). On the basis of these results, we - together with colleagues from different countries - have put forward the hypothesis that life-long latent infection with CMV accelerates the aging of the immune system. CMV infection should therefore be generally prevented in childhood by vaccination.

In view of age related accumulation of CD8+CD28- T cells we aimed at clarifying the question whether this specific T cell type is less or more prone to undergo cell death mediated by extrinsic and intrinsic factors. Our data demonstrate that resting ex vivo CD28-CD8+ T cells are more prone to undergo cell death mediated by extrinsic and intrinsic factors. The observed difference is caused by a panel of dysregulated miRNAs which we find to be differentially expressed in CD28-CD8+ T cells. In this context it was of interest to observe that CD8+CD28- T cells also had a decreased DNA repair capacity. Increased ability of CD8+ effector T cells to apoptosis inducing factors can be reversed by the cytokine IL-15 or by the polyamine spermidine.

Rescuing T cells with the help of IL-15 is alsointeresting in view of recent research on adaptive immune cells in the healthy human bone marrow (BM). The bone marrow is particularly rich of IL-15 and bone marrow IL-15 production is still higher in old age. Although BM has recently been attributed a key role in memory T cell maintenance, little is still known about the distribution, phenotype and function of human T cell subsets in the BM and how aging affects BM T cell function and survival. We now demonstrated that human BM T cells are in a heightened activation state and express a characteristic set of chemokine- and co-stimulatory receptors compared to peripheral blood (PB) T cells. T cells are found in close vicinity to IL-15 producing stromal cells and monocytes. Aging leads to a decline of naïve T cells and to an accumulation of cells with an effector/effector memory phenotype in the BM. Yet, “senescent” CD57-expressing effector CD8+ T cells do not occur in the BM of elderly persons. Gene array analysis revealed a potent network of inflammatory cytokines responsible for the increased  activation state and distinct phenotype of BM T cells in old age. Our results indicate that the BM environment is important for the maintenance of memory and effector T cells which may provide a line of defense during human aging.

In the field of vaccination, the immunology group was one of the first groups worldwide to point out that elderly persons do not have sufficient protection against diseases preventable by conventional vaccines such as tetanus (Nature Med 1998;4:870). In the following years this initial observation was complemented by retro- as well as prospective studies on the effects of different vaccines in old age. From these studies we have developed new vaccination strategies which have led to official vaccination recommendations in Austria specific for elderly persons.