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Selection of the cutaneous intraepithelial γδ+ T cell repertoire by a thymic stromal determinant

Nature Immunology volume 7, pages 843–850 (2006)Cite this article

Abstract

Intraepithelial lymphocytes constitute a group of T cells that express mainly monospecific or oligoclonal T cell receptors (TCRs). Like adaptive TCRαβ+ T cells, intraepithelial lymphocytes, a subset enriched in TCRγδ+ T cells, are proposed to be positively selected by thymically expressed self agonists, yet no direct evidence for this exists at present. Mouse dendritic epidermal T cells are prototypic intraepithelial lymphocytes, displaying an almost monoclonal TCRγδ+ repertoire. Here we describe an FVB substrain of mice in which this repertoire was uniquely depleted, resulting in cutaneous pathology. This phenotype was due to failure of dendritic epidermal T cell progenitors to mature because of a heritable defect in a dominant gene used by the thymic stroma to 'educate' the natural, skin-associated intraepithelial lymphocyte repertoire to be of physiological use.

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Figure 1: DETCs of FVB-Tac mice have an altered TCRγδ repertoire.
Figure 2: The altered DETC repertoire in FVB-Tac mice has functional consequences.
Figure 3: DETC precursors in FVB-Tac fetal thymus have defective maturation.
Figure 4: Chemokine receptor expression is altered in E16 FVB-Tac Vγ5+ thymocytes.
Figure 5: The defect in the FVB-Tac fetal thymus is confined to thymic stromal cells.
Figure 6: TCR ligation mimics normal fetal thymic stromal cells in allowing the maturation of FVB-Tac Vγ5+Vδ1+ fetal thymocytes.
Figure 7: Segregation of the DETC phenotype in FVB-Jax × FVB-Tac F1 and F1 × FVB-Tac backcrossed mice is consistent with control by a single autosomal dominant gene.

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Acknowledgements

We thank A. Bas, J.-J. Mention, R. Filler D. Pennington, B. Silva-Santos and E. Theodoridis for discussions. Supported by the National Institutes of Health (R01-A.R49282 and P30-AR041942 to R.E.T.) and Wellcome Trust (A.C.H. and S.D.B).

Author information

Authors and Affiliations

  1. Department of Dermatology and Yale Skin Disease Research Core Center, Yale University School of Medicine, New Haven, 06511, Connecticut, USA

    Julia M Lewis, Michael Girardi, Scott J Roberts & Robert E Tigelaar

  2. Peter Gorer Department of Immunobiology, King's College School of Medicine at Guy's Hospital, London, SE1 9RT, UK

    Susannah D Barbee & Adrian C Hayday

  3. Section of Immunobiology, Yale University School of Medicine, New Haven, 06511, Connecticut, USA

    Robert E Tigelaar

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  1. Julia M Lewis
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Contributions

All authors contributed to discussions of experimental design, data analysis and manuscript preparation; J.M.L. did all experimental studies unless otherwise indicated; S.R. prepared and analyzed gut IEL suspensions; S.D.B. purified, cloned and sequenced skin and uterine DNA; and R.E.T. did the semiquantitative analyses of fetal thymocyte chemokine receptor cDNA.

Corresponding author

Correspondence to Robert E Tigelaar.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

The majority of DETC in 'normal' mouse strains utilize Vγ5,Vδ1. (PDF 56 kb)

Supplementary Fig. 2

DETC repertoires in adult FVB-Jax and FVB-Tac mice. (PDF 307 kb)

Supplementary Fig. 3

Fetal thymocyte yields from E15-E17 FVB-Jax and FVB-Tac mice. (PDF 57 kb)

Supplementary Fig. 4

Increased apoptosis among Vγ5+ FVB-Tac fetal thymocytes. (PDF 129 kb)

Supplementary Fig. 5

FVB-Jax and FVB-Tac have equivalent maturation of Vδ1+ and Vδ4+ fetal thymocytes. (PDF 2207 kb)

Supplementary Fig. 6

Defect in Vγ5,Vδ1+ fetal thymocyte maturation in FVB-Tac is maintained in vitro. (PDF 62 kb)

Supplementary Table 1

Sequence analysis of uterine TCR Vγ6-Jγ1 and Vδ1-Jδ2 gene rearrangements. (PDF 43 kb)

Supplementary Table 2

Primers and PCR conditions used in chemokine gene expression analysis. (PDF 49 kb)

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Lewis, J., Girardi, M., Roberts, S. et al. Selection of the cutaneous intraepithelial γδ+ T cell repertoire by a thymic stromal determinant. Nat Immunol 7, 843–850 (2006). https://doi.org/10.1038/ni1363

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