T-cell generation by lymph node resident progenitor cells.

In the thymus, 2 types of Lin-Sca-1+ (lineage-negative stem cell antigen-1-positive) progenitors can generate T-lineage cells: c-Kit(hi) interleukin-7 receptor alpha-negative (c-Kit(hi)IL-7Ralpha-) and c-Kit(lo)IL-7Ralpha+. While c-Kit(hi)IL-7Ralpha- progenitors are absent, c-Kit(lo)IL-7Ralpha+ progenitors are abundant in the lymph nodes (LNs). c-Kit(lo)IL-7Ralpha+ progenitors undergo abortive T-cell commitment in the LNs and become arrested in the G1 phase of the cell cycle because they fail both to up-regulate c-myb, c-myc, and cyclin D2 and to repress junB, p16(INK4a), and p21(Cip1/WAF). As a result, development of LN c-Kit(lo)IL-7Ralpha+ progenitors is blocked at an intermediate CD44+CD25lo development stage in vivo, and LN-derived progenitors fail to generate mature T cells when cultured with OP9-DL1 stromal cells. LN stroma can provide key signals for T-cell development including IL-7, Kit ligand, and Delta-like-1 but lacks Wnt4 and Wnt7b transcripts. LN c-Kit(lo)IL-7Ralpha+ progenitors are able to generate mature T cells when cultured with stromal cells producing wingless-related MMTV integration site 4 (Wnt4) or upon in vivo exposure to oncostatin M whose signaling pathway intersects with Wnt. Thus, supplying Wnt signals to c-Kit(lo)IL-7Ralpha+ progenitors may be sufficient to transform the LN into a primary T-lymphoid organ. These data provide unique insights into the essence of a primary T-lymphoid organ and into how a cryptic extrathymic T-cell development pathway can be amplified.