Reduced EBF expression underlies loss of B cell potential of hematopoietic progenitors with age.
Abstract
Summary Aging is accompanied by a reduction in the generation of B lymphocytes leading to impaired immune responses. In this study we have investigated whether the decline in B lymphopoiesis is due to age-related defects in the hematopoietic stem cell compartment. The ability of hematopoietic stem cells from old mice to generate B cells, as measured in vitro, is decreased 2-5 fold, while myeloid potential remains unchanged. This age-related decrease in B cell potential is more marked in common lymphoid progenitors (CLP) and was associated with reduced expression of the B-lineage specifying factors, EBF and Pax5. Notably, retrovirus-mediated expression of EBF complemented the age-related loss of B cell potential in CLP isolated from old mice. Furthermore, transduction of CLP from old mice with a constitutively active form of STAT5 restored both EBF and Pax5 expression and increased B cell potential. These results are consistent with a mechanism whereby reduced expression of EBF with age decreases the frequency with which multipotent hematopoietic progenitors commit to a B cell fate, without altering their potential to generate myeloid cells.