Dynamic Clonal Hematopoiesis and Functional T-cell Immunity in a Super-centenarian

Abstract

AbstractThe aged hematopoietic system is characterized by decreased immuno-competence and by a reduced number of hematopoietic stem cells (HSCs) that actively generates new blood cell (age-related clonal hematopoiesis, ARCH). While both aspects are commonly associated with an increased risk of aging-related diseases, it is currently unknown to what extent these aspects co-occur during exceptional longevity. Here, we investigated these aspects in blood cells of an immuno-hematopoietically normal female who reached 111 years. Blood samples were collected across a 9-year period at ages 103, 110 and 111 years. We applied several genetic sequencing approaches to investigate clonality in peripheral blood samples and sorted cell subsets. Immuno-competence was characterized using flow cytometry, T-cell receptor excision circle (TREC) assays, and in vitro proliferation assays. We identified a single DNMT3A-mutated HSC clone with a complex subclonal architecture and observed ongoing subclonal dynamics within the 9-year timeframe of our sampling. The mutated HSC generated 78-87% myeloid cells, 6-7% of the B-cells, 6% of CD8+ T-cells, and notably 22% of the CD4+ T-cells. Intriguingly, we found that T-cells were capable of robust proliferation when challenged in vitro. Moreover, we observed a surprisingly high TREC content, indicative of recent generation of naive T-cells. Concluding, we observed long-term stability of extreme ARCH with ongoing clonal dynamics combined with functional T-cell immunity. Our results indicate that extreme ARCH does not compromise immuno-competence and that a clonally expanded CD4+ T-cell subset may serve as a potential hallmark of the supercentenarian immune system.Key pointsLongitudinal blood sampling from a female aged 103-111 revealed a dynamic clonal hematopoiesis contributing to myeloid and lymphoid subsetsDespite the highly advanced age and extreme clonal hematopoiesis we observed functional T-cell immunity