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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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).
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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.
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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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DOI: https://doi.org/10.1038/ni1363
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