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Requirement for Notch1 signals at sequential early stages of intrathymic T cell development

Nature Immunology volume 6, pages 671–679 (2005)Cite this article

An Erratum to this article was published on 01 September 2005

Abstract

Signaling through the transmembrane Notch1 receptor directs thymus-seeding progenitors (TSPs) to suppress their B cell potential and 'choose' the T cell fate. Present paradigms suggest that TSPs are contained in the multipotent early T lineage precursor (ETP) subset of thymocytes. However, we show here that the B cell potential of ETPs was not augmented in microenvironments that limited Notch1 activation. Furthermore, low-threshold Notch1 signals suppressed B cell production by TSPs before they reached the ETP stage. Notch1 signals of a higher threshold were needed to drive proliferation of ETPs and development into CD4+CD8+ double-positive thymocytes. Thus, TSPs can be differentiated from all previously identified early T cell progenitors by their robust B cell potential and exquisite sensitivity to Notch1 signals.

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Figure 1: Failure of ETPs to produce B cells in L-Fng-transgenic thymic lobes.
Figure 2: Minimal B cell potential of ETPs in the bone marrow.
Figure 3: High expression of Hes1 by all DN thymocyte subsets.
Figure 4: Paucity of ETPs and DN2 thymocytes in L-Fng-transgenic mice.
Figure 5: DN1 thymocyte subsets in L-Fng-transgenic mice.
Figure 6: Cells with an early B cell progenitor phenotype in L-Fng-transgenic thymi.
Figure 7: Notch1+/− progenitors are highly sensitive transgenic L-Fng.
Figure 8: Production of ETPs and thymic B cells from HSCs is differentially sensitive to decreased Notch1 'dosage'.

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Acknowledgements

We thank C. Paige (Ontario Cancer Institute, Toronto, Canada) for OP9 cells; J. Dick and M. Doedens (University Health Network, Toronto, Canada) as well as L. Nutter for help with intrafemoral injections; S. Zhao for cell sorting; H. Petrie (University of Miami, Miami, Florida), W. Pear and A. Bhandoola (University of Pennsylvania, Philadelphia, Pennsylvania) for sharing data before publication; H. Petrie for Ter119; and J. Danska and M. Anderson (Sunnybrook & Women's College Hospital, Toronto, Canada) for comments on the manuscript. Supported by the Canadian Institutes of Health Research (C.J.G.) and Hospital for Sick Children (Restracom Studentship to J.Y.).

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Authors and Affiliations

  1. Program in Developmental Biology, Hospital for Sick Children Research Institute, Toronto, M5G 1X8, Ontario, Canada

    Joanne B Tan, Ioana Visan, Julie S Yuan & Cynthia J Guidos

  2. Department of Immunology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Joanne B Tan, Ioana Visan, Julie S Yuan & Cynthia J Guidos

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Correspondence to Cynthia J Guidos.

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Supplementary information

Supplementary Fig. 1

Inefficient Production of DP Thymocytes from Notch1+/− HSCs in Mixed BM Chimeras. (PDF 82 kb)

Supplementary Fig. 2

Normal Steady State Production of Thymic T and B Cells in Notch1+/− Mice. (PDF 95 kb)

Supplementary Fig. 3

Analysis of Donor Contribution to HSCs and DN Thymocyte Subsets in Mixed Chimeras. (PDF 101 kb)

Supplementary Fig. 4

Effect of Transgenic L-Fng on Committed B Cell Progenitors. (PDF 70 kb)

Supplementary Table 1

ETPs Efficiently Reconstitute All Thymic Subsets in WT and Tg+ Hosts. (PDF 52 kb)

Supplementary Methods (PDF 62 kb)

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Tan, J., Visan, I., Yuan, J. et al. Requirement for Notch1 signals at sequential early stages of intrathymic T cell development. Nat Immunol 6, 671–679 (2005). https://doi.org/10.1038/ni1217

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