ADAM17 deletion in thymic epithelial cells alters aire expression without affecting T cell developmental progression

David M. Gravano, Bryce T. McLelland, Keisuke Horiuchi, Jennifer O. Manilay

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Cellular interactions between thymocytes and thymic stromal cells are critical for normal T cell development. Thymic epithelial cells (TECs) are important stromal niche cells that provide essential growth factors, cytokines, and present self-antigens to developing thymocytes. The identification of genes that mediate cellular crosstalk in the thymus is ongoing. One candidate gene, Adam17, encodes a metalloprotease that functions by cleaving the ectodomain of several transmembrane proteins and regulates various developmental processes. In conventional Adam17 knockout mice, a noncell autonomous role for ADAM17 in adult T cell development was reported, which strongly suggested that expression of ADAM17 in TECs was required for normal T cell development. However, knockdown of Adam17 results in multisystem developmental defects and perinatal lethality, which has made study of the role of Adam17 in specific cell types difficult. Here, we examined T cell and thymic epithelial cell development using a conditional knockout approach. Methodology/Principal Findings: We generated an Adam17 conditional knockout mouse in which floxed Adam17 is deleted specifically in TECs by Cre recombinase under the control of the Foxn1 promoter. Normal T cell lineage choice and development through the canonical ab T cell stages was observed. Interestingly, Adam17 deficiency in TECs resulted in reduced expression of the transcription factor Aire. However, no alterations in the patterns of TEC phenotypic marker expression and thymus morphology were noted. Conclusions/Significance: In contrast to expectation, our data clearly shows that absence of Adam17 in TECs is dispensable for normal T cell development. Differentiation of TECs is also unaffected by loss of Adam17 based on phenotypic markers. Surprisingly, we have uncovered a novel genetic link between Adam17and Aire expression in vivo. The cell type in which ADAM17 mediates its non-cell autonomous impact and the mechanisms by which it regulates intrathymic T cell development remain to be identified.

Original languageEnglish
Article numbere13528
JournalPLoS One
Volume5
Issue number10
DOIs
Publication statusPublished - 2010

Fingerprint

T-cells
epithelial cells
T-lymphocytes
Epithelial Cells
T-Lymphocytes
Thymus
thymocytes
Thymocytes
Stromal Cells
Knockout Mice
Thymus Gland
Genes
transmembrane proteins
ADAM17 Protein
stromal cells
mice
Autoantigens
Metalloproteases
metalloproteinases
Cell Lineage

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

ADAM17 deletion in thymic epithelial cells alters aire expression without affecting T cell developmental progression. / Gravano, David M.; McLelland, Bryce T.; Horiuchi, Keisuke; Manilay, Jennifer O.

In: PLoS One, Vol. 5, No. 10, e13528, 2010.

Research output: Contribution to journalArticle

Gravano, David M. ; McLelland, Bryce T. ; Horiuchi, Keisuke ; Manilay, Jennifer O. / ADAM17 deletion in thymic epithelial cells alters aire expression without affecting T cell developmental progression. In: PLoS One. 2010 ; Vol. 5, No. 10.
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