Long-lived plasma cells regulate patterns of hematopoiesis in aging.

Abstract In both humans and mice, aging results in significant alterations to the patterns of bone marrow hematopoiesis. This is highlighted by a precipitous reduction in B lymphopoiesis while myelopoiesis is enhanced. Treatment of young mice with factors such as GM-CSF or IL-1 can skew hematopoiesis towards myeloid development. This suggests that imbalances in the relative concentrations of various cytokines such as inflammatory mediators, whose production is thought to increase with age, could contribute to suppressed lymphoid and enhanced myeloid development in aging. In this case, the resulting stimulation of myelopoiesis would dominate the limited number of niches in the bone marrow environment at the expense of lymphopoiesis. However, whether the age-related decline in lymphopoiesis and increase in myelopoiesis are linked or represent distinct processes is not known. We observed that long-lived plasma cells from old mice acquire an inflammatory gene signature and accumulate in the bone marrow. Addition of long-lived plasma cells to long-term in vitro cultures demonstrated the ability of these cells to promote granulopoiesis from hematopoietic stem cells as well as myeloid progenitors. However, while depletion of long-lived plasma cells in old mice by injection of anti-CD138 antibodies resulted in a significant reduction in myeloid development, B lymphopoiesis remained suppressed. These data demonstrate a previously unappreciated ability of inflammatory plasma cells to stimulate myelopoiesis and provide evidence that, in the context of aging, enhanced myelopoiesis and depressed lymphopoiesis are distinct, independently regulated processes.