Lymphoid stem cells (also termed common lymphoid progenitors or CLPs) are clearly defined by their ability to differentiate exclusively into each type of lymphocyte. Our preliminary data suggest that numbers of CLPs in adult mouse bone marrow are significantly reduced in aged mice, suggesting that previously reported defects in lymphocyte development in aged mice are the result of defects in the factors governing the maintenance and/or differentiation of CLPs. We will explore these possibilities with three specific aims.
In Aim 1, we will utilize DNA content analysis of young versus old CLPs isolated by cell sorting and in vivo BrdU labeling to determine whether our observation of reduced cellularity of CLPs in aged mice is due to decreases in proliferation among CLPs or decreases in CLP generation versus survival.
In Aim 2, we will utilize IL-7 driven stromal cell-free cultures to assess whether decreases in CLP cellularity in aged mice reflects diminished responsiveness to IL-7.
In Aim 3, we will establish BM chimeras to determine whether age-associated decreases in frequencies of CLPs reflect cell autonomous versus environmental defects.
| Allman, David; Sambandam, Arivazhagan; Kim, Sungjune et al. (2003) Thymopoiesis independent of common lymphoid progenitors. Nat Immunol 4:168-74 |
| Miller, Juli P; Allman, David (2003) The decline in B lymphopoiesis in aged mice reflects loss of very early B-lineage precursors. J Immunol 171:2326-30 |
| Miller, Juli P; Izon, David; DeMuth, William et al. (2002) The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. J Exp Med 196:705-11 |
