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Regulation of T lymphopoiesis by Notch1 and Lunatic fringe–mediated competition for intrathymic niches

Nature Immunology volume 7, pages 634–643 (2006)Cite this article

Abstract

Notch1 activation regulates T lineage commitment and early T cell development. Fringe glycosyltransferases alter the sensitivity of Notch receptors to Delta-like versus Jagged Notch ligands, but their functions in T lymphopoiesis have not been defined. Here we show that developmental stage–specific expression of the glycosyltransferase lunatic fringe (Lfng) is required for coordination of the access of T cell progenitors to intrathymic niches that support Notch1-dependent phases of T cell development. Lfng-null progenitors generated few thymocytes in competitive assays, whereas Lfng overexpression converted thymocytes into 'supercompetitors' with enhanced binding of Delta-like ligands and blocked T lymphopoiesis from normal progenitors. We suggest that the ability of Lfng and Notch1 to control progenitor competition for limiting cortical niches is an important mechanism for the homeostatic regulation of thymus size.

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Figure 1: Expression of endogenous and transgenic Lfng mRNA in thymocyte subsets.
Figure 2: Lfng−/− progenitors fail to efficiently reconstitute the thymus in mixed chimeras.
Figure 3: Increased binding of Dll1 by Tg+ thymocytes.
Figure 4: Transgenic Lfng converts T cell precursors into 'supercompetitors'.
Figure 5: Lfng−/− progenitors generate T cells on OP9-Dll1 stromal cells.
Figure 6: Lfng-Notch1 interactions regulate access of T cell progenitors to DN3 niches.
Figure 7: Notch1 heterozygosity reduces B cell development and restores T cell development in Tg+ thymic lobes.
Figure 8: Tg+ DP thymocytes block TSP access to CMJ niches.

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Acknowledgements

We thank J.-C. Zuniga-Pflucker (Sunnybrook and Women's College Hospital, Toronto, Canada) for OP9-GFP and OP9-Dll1 stromal cells; S. Egan and J. Danska (Hospital for Sick Children, Toronto, Canada) and A. Bhandoola (University of Pennsylvania, Philadelphia, Pennsylvania) for discussions and critical reading of the manuscript; and K. Yasutomo (University of Tokushima, Tokushima, Japan) for sharing unpublished data. Supported by the Canadian Institutes of Health Research (C.J.G.) and the Hospital for Sick Children (J.S.Y. and J.B.T.)

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  1. Program in Developmental Biology, Hospital for Sick Children Research Institute, and Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, M5G 1L7, Ontario, Canada

    Ioana Visan, Joanne B Tan, Julie S Yuan, James A Harper, Ute Koch & Cynthia J Guidos

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Contributions

I.V., J.B.T., J.S.Y., J.A.H. and U.K. did experimental work and analyzed data; C.J.G. supervised the experimental work; and I.V. and C.J.G. wrote the manuscript.

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Correspondence to Cynthia J Guidos.

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Supplementary information

Supplementary Fig. 1

Niche exclusion model. (PDF 161 kb)

Supplementary Table 1

Production of DP and B220+ thymocytes from Lfng−/− FL in single versus mixed chimeras. (PDF 45 kb)

Supplementary Table 2

DP thymocyte production from Lfng Tg+ BM progenitors alone or in competition with non-transgenic BM progenitors. (PDF 46 kb)

Supplementary Table 3

DP thymocyte and B cell production after injection of non-transgenic or Lfng Tg+ BM progenitors into unconditioned hosts. (PDF 53 kb)

Supplementary Table 4

Effect of Notch1 heterozygosity on abundance of thymic B cells and DP thymocytes in non-transgenic and Lfng Tg+ mice. (PDF 51 kb)

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Visan, I., Tan, J., Yuan, J. et al. Regulation of T lymphopoiesis by Notch1 and Lunatic fringe–mediated competition for intrathymic niches. Nat Immunol 7, 634–643 (2006). https://doi.org/10.1038/ni1345

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