A Role of CXC Chemokine Ligand 12/Stromal Cell-Derived Factor-1/Pre-B Cell Growth Stimulating Factor and Its Receptor CXCR4 in Fetal and Adult T Cell Development in Vivo

Abstract

The functions of a chemokine CXC chemokine ligand (CXCL) 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its physiologic receptor CXCR4 in T cell development are controversial. In this study, we have genetically further characterized their roles in fetal and adult T cell development using mutant and chimeric mice. In CXCL12−/− or CXCR4−/− embryos on a C57BL/6 background, accumulation of T cell progenitors in the outer mesenchymal layer of the thymus anlage during initial colonization of the fetal thymus was comparable with that seen in wild-type embryos. However, the expansion of CD3−CD4−CD8− triple-negative T cell precursors at the CD44−CD25+ and CD44−CD25− stages, and CD4+CD8+ double-positive thymocytes was affected during embryogenesis in these mutants. In radiation chimeras competitively repopulated with CXCR4−/− fetal liver cells, the reduction in donor-derived thymocytes compared with wild-type chimeras was much more severe than the reduction in donor-derived myeloid lineage cells in bone marrow. Triple negative CD44+CD25+ T cell precursors exhibited survival response to CXCL12 in the presence of stem cell factor as well as migratory response to CXCL12. Thus, it may be that CXCL12 and CXCR4 are involved in the expansion of T cell precursors in both fetal and adult thymus in vivo. Finally, enforced expression of bcl-2 did not rescue impaired T cell development in CXCR4−/− embryos or impaired reconstitution of CXCR4−/− thymocytes in competitively repopulated mice, suggesting that defects in T cell development caused by CXCR4 mutation are not caused by reduced expression of bcl-2.

Highly Pathogenic Influenza Virus Infection of the Thymus Interferes with T Lymphocyte Development

“…CXCL12, which is recognized by the CXCR4 receptor, is an essential prerequisite for functional thymocyte migration (33). CXCL12 is produced by both cortical and medullar epithelial cells, and recent studies underline the urgent need for CXCL12/CXCR4 pathway in T lymphocyte development in vivo (34). In single-positive CD4 2 CD8 + or CD4 + CD8 2 T lymphocytes, the expression rate of CXCR4 is reduced, which supports the outflow of naive T lymphocytes into the periphery (35).…”

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…T and B lymphocytes utilize CXCR4 for trafficking and homing to distinct microenvironments within lymphoid tissues and the thymus during development and immune surveillance. 82,132 Another general concern regarding the use of CXCR4 antagonists in cancer patients is the mobilization of normal progenitor cells, such as HSC from their microenvironments to the blood. Mobilized HSCs that are normally protected in marrow niches would be exposed to the effects of cytotoxic drugs in trials where CXCR4 antagonists are administered along with cytotoxic drugs, which could result in prolonged cytopenias.…”

The preTCR‐dependent DN3 to DP transition requires Notch signaling, is improved by CXCL12 signaling and is inhibited by IL‐7 signaling

“…Thus, proliferation and differentiation of DN3 cells into DPs on plate-bound DL4 are preTCR dependent. The finding that sorted DN3 cells from Rag-2-deficient mice did not even survive for 3 days in the present culture system further supports this conclusion.It was recently suggested that PI3 kinase signaling mediated by CXCR4 is also involved in the DN3 to DP transition [40][41][42]. To evaluate the contribution of CXCL12 during this differentiation step in the present culture system, we sorted DN3 cells and cultured them in the presence of 10 nM CXCL12.…”

“…It was recently suggested that PI3 kinase signaling mediated by CXCR4 is also involved in the DN3 to DP transition [40][41][42]. To evaluate the contribution of CXCL12 during this differentiation step in the present culture system, we sorted DN3 cells and cultured them in the presence of 10 nM CXCL12.…”