Mechanisms of altered B lymphopoiesis in senescence

Advancing age is accompanied by a decrease in the numbers of bone marrow pre-B cells in mice. Using information and technologies developed in the more recent past, this study has re-examined the stages of B cell developmental impairment and addressed possible mechanisms responsible for the aging phenomenon. Ex vivo analysis of bone marrow B cell precursors revealed two distinct patterns of disruption of B cell lymphopoiesis. In the first pattern, moderate decreases (∼50%) were seen in the late pre-B cell compartment only. The second pattern revealed severe decreases (\u3e80%) in late pre-B cells, and this was accompanied by a decrease in pro-B cells. In both types of altered B cell lymphopoiesis, the frequencies of cells in active cell cycle was normal among all subsets of precursors. Of interest, aged mice with severely reduced pre-B cell numbers show increased susceptibility to apoptosis of both pro-B and pre-B cells. Expression of the surrogate light (SL) chain components is decreased at both the mRNA and protein levels in aged pro-B/early pre-B cells. Since the decreases seen in SL expression occur at the mRNA level, we examined the status of transcription factors important for SL expression in particular, and B lymphopoiesis in general, in aged B cell precursors. Aged B cell precursors expanded in culture with IL-7 showed decreased expression of the transcription factors Pax-5/BSAP and E2A/E47. Notably, diminished E2A/E47 correlated with lambda5 expression, which, in turn, correlated with ex vivo pre-B cell numbers. Both microenvironmental and cell intrinsic factors contributed to reduced expansion of aged pro-B/early pre-B cells in response to IL-7. We propose a model of impaired B cell lymphopoiesis in aging, as follows. In cases with moderate pre-B cell depletion, recruitment into the late pre-B cell compartment is diminished. This is possibly due to decreased expression of the SL chain components, leading to insufficient levels of the preBCR to mediate differentiation into the late pre-B cell stage. However, once selected for further maturation, the cells proliferate normally. Additionally, in cases with severe pre-B cell depletion, decreases in the earliest precursors, the pro-B cells, leads to further depletion in the subsequent precursor compartments. Thus, decreases in B cell precursors manifest as a failure of selection into differentiation, in all cases at the pre-B cell level, and in severely depleted mice, also at the pro-B cell stage