RESTORING YOUTHFUL CELLULAR IMMUNITY BY REJUVENATION OF AGED HEMATOPOIETIC STEM CELLS

Aging-associated remodeling of the immune system results in its decreased functionality. Most prominent in man and mice is a significant reduction of naïve CD8 T cells in old individuals, accompanied by a decreased responsiveness to infection or vaccination. Aging of hematopoietic stem cells (HSCs) could be a crucial factor in the age-associated immune remodeling, as old HSC inefficiently produce lymphoid progenitor cells. In vitro inhibition of the Cdc42 Rho-GTPase activity in aged HSCs with the pharmacological compound CASIN led to their sustained morphological rejuvenation. In this study, we ask if and how old HSCs directly affect the remodeling of the old immune system and whether CASIN-mediated rejuvenation of aged HSCs contributes to restoring the functionality of an aged immune system. To analyze this, young, old and rejuvenated old HSCs (isolated from immune-competent young or old B6.SJL mice) were transplanted into T- and B- cell deficient young RAG1-/- mice. Three months after transplantation, the immune system developed from young and CASIN-treated old HSCs was comparable to a youthful immune system, whereas old HSCs reconstituted an aged-like immune system as is indicated e.g., by appropriate proportions of naïve CD8+ T or regulatory Foxp3+ CD4+ Treg cells. Most interestingly, the immune system developed from CASIN-treated old, but not from old HSCs efficiently respond to vaccination, thus we could restore de novo priming of HBV-core-specific effector CD8+ T cell responses. Rejuvenation of old HSCs is therefore an attractive strategy to manipulate the age-associated remodeling of the immune system and to restore its immune competence.