T-cell generation by lymph node resident progenitor cells

Abstract

In the thymus, 2 types of Lin–Sca-1+ (lineage-negative stem cell antigen-1–positive) progenitors can generate T-lineage cells: c-Kithi interleukin-7 receptor α–negative (c-KithiIL-7Rα–) and c-KitloIL-7Rα+. While c-KithiIL-7Rα– progenitors are absent, c-KitloIL-7Rα+ progenitors are abundant in the lymph nodes (LNs). c-KitloIL-7Rα+ 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, p16INK4a, and p21Cip1/WAF. As a result, development of LN c-KitloIL-7Rα+ 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-KitloIL-7Rα+ 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-KitloIL-7Rα+ 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.