Restoring the functionality of the old immune system by rejuvenation of aged hematopoietic stem cells

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Restoring the functionality of the old immune system by rejuvenation of aged hematopoietic stem cells. Aging is associated with a variety of changes in the immune system summarized as aging-associated immune remodeling (AAIR). AAIR is thought to be a major cause of the reduced function of the immune system in the elderly. While the role of thymic involution has been studied and discussed as an important contributing factor to AAIR, there is only limited information available on the extent to which aging of hematopoietic stem cells (HSCs), from which lymphocytes are ultimately derived, contributes to AAIR. Aging of HSCs is in part driven by elevated activity of the small RhoGTPase Cdc42. In vitro treatment of aged HSCs with the Cdc42 activity inhibitor CASIN resulted in long-term epigenetic and morphological changes that may drive the reconstitution of a youthful and immune-competent immune system. The proposal aims to elucidate (i) the development of complex immune systems stemming from young or aged HSCs, also under the influence of an aged bone marrow niche.(ii) molecular and mechanistic links between HSC aging and the phenotypic and functional changes in the aged immune system (iii) in vitro rejuvenation of aged HSCs with the pharmacological compound CASIN. Of particular interest are CASIN-induced molecular signatures in aged HSCs and the corresponding HSC-derived immune cells that shift their ´aged´ differentiation program towards a youthful immune system capable of mounting strong responses to vaccination. To study the generation of a complex immune system from HSCs, we use a novel HSC-transplantation model in T- and B-cell deficient young RAG1-/- hosts. We will transplant young, aged or CASIN treated aged HSCs into RAG1-/- hosts to analyze distinct T-cell subsets. We will determine their transcriptome, their epigenetic changes as well as changes in their function. This model allows us to directly characterize the selective repopulation of T-cell subsets developing from donor HSCs under well-defined conditions and also to evaluate the functiona of the reconstituting immune system in vaccination studies (e.g., Protein-based vaccination). In a final set of experiment, we will investigate in as much aging of the stem cell niche also contributes to AAIR, as aging of the niche also influences aging of HSCs. In summary, these studies may help to design specific protocols that attenuate or even revert AAIR by rejuvenation of aged HSCs.