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Blood, 15 January 2002, Vol. 99, No. 2, pp. 546-554
IMMUNOBIOLOGY
Stromal cell-derived factor 1/CXCR4 signaling is critical for
early human T-cell development
Carmen Hernández-López,
Alberto Varas,
Rosa Sacedón,
Eva Jiménez,
Juan José Muñoz,
Agustín G. Zapata, and
Angeles Vicente
From the Department of Cell Biology, Faculty of
Biology, and Department of Cell Biology, Faculty of Medicine,
Complutense University of Madrid, Madrid, Spain.
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.
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