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.
Terra
Rafik
R
Institute of Research in Immunology and Cancer, University of Montreal, QC, Canada.
Louis
Isabelle
I
Le Blanc
Richard
R
Ouellet
Sophie
S
Zúñiga-Pflücker
Juan Carlos
JC
Perreault
Claude
C
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008198:Lymph Nodes / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D053683:Oncostatin M; D010455:Peptides / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D013234:Stem Cells / Q000166:cytology* / Q000276:immunology*; D017154:Stromal Cells / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology; D051153:Wnt Proteins; D060528:Wnt4 Protein
D006023:Glycoproteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C508352:Osm protein, mouse; D010455:Peptides; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse; C095937:Wnt7b protein, mouse; D053683:Oncostatin M; D019009:Proto-Oncogene Proteins c-kit