Primitive Lymphoid Progenitors in Bone Marrow with T Lineage Reconstituting Potential

Abstract

Multiple subsets of the bone marrow contain T cell precursors, but it remains unclear which is most likely to replenish the adult thymus. Therefore, RAG-1+ early lymphoid progenitors (RAG-1+ ELP), and CD62L/L-selectin+ progenitors (LSP), as well as common lymphoid progenitors from C57BL6-Thy1.1-RAG-1/GFP mouse bone marrow were directly compared in transplantation assays. The two c-Kithigh populations vigorously regenerated the thymus and were superior to common lymphoid progenitors in magnitude and frequency of thymic reconstitution. Regeneration was much faster than the 22 days described for transplanted stem cells, and RAG-1+ ELP produced small numbers of lymphocytes within 13 days. As previously reported, LSP were biased to a T cell fate, but this was not the case for RAG-1+ ELP. Although RAG-1+ ELP and LSP had reduced myeloid potential, they were both effective progenitors for T lymphocytes and NK cells. The LSP subset overlapped with and included most RAG-1+ ELP and many RAG-1−TdT+ ELP. LSP and RAG-1+ ELP were both present in the peripheral circulation, but RAG-1+ ELP had no exact counterpart among immature thymocytes. The most primitive of thymocytes were similar to Lin−c-KithighL-selectin+TdT+RAG-1− progenitors present in the marrow, suggesting that this population is normally important for sustaining the adult thymus.

Selective Thymus Settling Regulated by Cytokine and Chemokine Receptors

“…had accelerated T lineage kinetics but generated fewer peak progeny for a shorter period of time than MPP (Fig. 2, A and C), as expected from past work with irradiated recipient mice (14,40,47,54). Interestingly, although CLP are phenotypically c-Kit low , they up-regulated c-Kit to generate c-Kit high ETP and DN2 thymocytes by day 8 after transfer.…”

“…We were unable to find CLP in the bloodstream of adult mice (18). However, a new study suggests that low numbers of CLP-like cells may circulate (54). Therefore, CLP may directly contribute to T cell development, although they are much less efficient T lineage progenitors than MPP.…”

Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development

“…Consistent with this model, we reported previously that the Flk2 + subset of CLPs has robust T-cell potential (Karsunky et al 2008), and that it is the predominant source of T cells within the bone marrow in transplantation experiments . However, other studies have suggested that CLPs predominantly differentiate into B cells, and that a population upstream of CLPs, the multipotent progenitor (MPP, sometimes called LMPP [lymphoid-primed MPP]), is the major source of T-cell progenitors from the bone marrow (Schwarz and Bhandoola 2004;Perry et al 2006;Lai and Kondo 2007;Wada et al 2008). These contradictory findings may have resulted from B-cell-biased progenitors that copurify and contaminate preparations of CLPs.…”

Hematopoietic developmental pathways: on cellular basis

“…The LMPP, the ELP and the CLP are detectable in peripheral blood, whereas the CLP-2 has not been found in the blood (Schwarz and Bhandoola, 2004;Perry et al, 2006;Krueger and von Boehmer, 2007;Umland et al, 2007). Recently, a novel T-lineage-committed progenitor subset presumably downstream of the CLP-2 was found in adult murine blood.…”