Stromal cell-derived factor 1/CXCR4 signaling is critical for early human T-cell development.
The present study investigated the potential role of stromal cell-derived factor 1 (SDF-1) in human intrathymic T-cell differentiation. Results show that SDF-1 is produced by human thymic epithelial cells from the subcapsular and medullary areas, and its receptor, CXCR4, is up-regulated on CD34(+) precursor cells committed to the T-cell lineage. Chimeric human-mouse fetal thymus organ culture (FTOC) seeded with purified CD34(+) thymic progenitors and treated with neutralizing antibodies against SDF-1 or CXCR4 showed a significant reduction of the number of human thymocytes and an arrested thymocyte differentiation in the transition between CD34(+) precursor cells and CD4(+) immature thymocytes. SDF-1-treated FTOC showed an increase of human thymocyte numbers, mainly affecting the most immature subpopulations. Moreover, these results suggest that CXCR4/SDF-1 signaling is not critical for the CD34(+) cell precursor recruitment to the thymus. On the other hand, SDF-1 significantly increased the viability of CD34(+) T-cell precursors modulating the expression of BCL-2 and BAX genes, and stimulated the proliferation of CD34(+) thymic precursor cells, particularly in synergy with interleukin 7 (IL-7), but not with other cytokines, such as stem cell factor or flt3-ligand. Accordingly, only IL-7 was able to up-regulate CXCR4 expression on CD34(+) thymic progenitors. In addition, deprivation of SDF-1 partially inhibited human thymocyte expansion induced by IL-7 in human-mouse FTOC. This study indicates that SDF-1/CXCR4 signaling is required for the survival, expansion, and subsequent differentiation of human early thymocytes and identifies a new mechanism by which IL-7 mediates its effects on human thymopoiesis.
Hernández-López
Carmen
C
Department of Cell Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain.
Varas
Alberto
A
Sacedón
Rosa
R
Jiménez
Eva
E
Muñoz
Juan José
JJ
Zapata
Agustín G
AG
Vicente
Angeles
A
D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002470:Cell Survival; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000502:physiology*; D002675:Child, Preschool; D018920:Coculture Techniques; D016207:Cytokines / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D019254:Genes, bcl-2; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007231:Infant, Newborn; D015851:Interleukin-7 / Q000494:pharmacology; D018655:Lymphocyte Count; D051379:Mice; D016513:Mice, SCID; D009924:Organ Culture Techniques; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000378:metabolism; D013950:Thymus Gland / Q000196:embryology / Q000254:growth & development / Q000276:immunology* / Q000648:ultrastructure; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; C494827:Bax protein, mouse; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D015851:Interleukin-7; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019718:Receptors, CXCR4; D051028:bcl-2-Associated X Protein