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Published on: December 16, 2013
Signal via lymphotoxin-beta R on bone marrow stromal cells is required for an early checkpoint of NK cell development
1Department of Pathology and Neurology, University of Chicago, Chicago, IL 60637, USA.
Abstract:
NK cells play an important role in the immune system but the cellular and molecular requirements for their early development are poorly understood. Lymphotoxin-alpha (LTalpha)(-/-) and LTbetaR(-/-) mice show a severe systemic reduction of NK cells, which provides an excellent model to study NK cell development. In this study, we show that the bone marrow (BM) or fetal liver cells from LTalpha(-/-) or LTbetaR(-/-) mice efficiently develop into mature NK cells in the presence of stromal cells from wild-type mice but not from LTalpha(-/-) or LTbetaR(-/-) mice. Direct activation of LTbetaR-expressing BM stromal cells is shown to promote to early NK cell development in vitro. Furthermore, the blockade of the interaction between LT and LTbetaR in adult wild-type mice by administration of LTbetaR-Ig impairs the development of NK cells in vivo. Together, these results indicate that the signal via LTbetaR on BM stromal cells by membrane LT is an important pathway for early NK cell development.
Insights
The development of Natural Killer (NK) cells is crucial for immunity. This study reveals that Lymphotoxin-beta receptor (LTbetaR) signaling on bone marrow stromal cells is essential for early NK cell development.
Area of Science:
- Immunology
- Cell Biology
Background:
- Natural Killer (NK) cells are vital immune components.
- Early NK cell development mechanisms are not fully understood.
- Lymphotoxin-alpha (LTalpha) and its receptor (LTbetaR) knockout models exhibit reduced NK cell populations.
Purpose of the Study:
- To investigate the role of lymphotoxin signaling in early NK cell development.
- To identify the cellular and molecular requirements for NK cell generation.
Main Methods:
- Utilized LTalpha(-/-) and LTbetaR(-/-) mice to study NK cell development.
- Co-cultured bone marrow or fetal liver cells with stromal cells in vitro.
- Activated LTbetaR-expressing bone marrow stromal cells directly.
- Administered LTbetaR-Ig to block LT/LTbetaR interaction in vivo.
Main Results:
- NK cell development occurred efficiently when LTalpha(-/-) or LTbetaR(-/-) cells were cultured with wild-type stromal cells, but not with LTalpha(-/-) or LTbetaR(-/-) stromal cells.
- Direct activation of LTbetaR-expressing stromal cells enhanced early NK cell development in vitro.
- Blocking LT/LTbetaR interaction in adult wild-type mice impaired NK cell development in vivo.
Conclusions:
- The signaling pathway involving Lymphotoxin-beta receptor (LTbetaR) on bone marrow stromal cells, mediated by membrane Lymphotoxin (LT), is critical for early NK cell development.
- LTbetaR signaling on stromal cells is a key regulator of NK cell homeostasis.
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