Frontiers in Immunology (Mar 2022)

Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium

  • Ken-ichi Hirano,
  • Hiroyuki Hosokawa,
  • Hiroyuki Hosokawa,
  • Takashi Yahata,
  • Takashi Yahata,
  • Kiyoshi Ando,
  • Kiyoshi Ando,
  • Masayuki Tanaka,
  • Jin Imai,
  • Masaki Yazawa,
  • Masato Ohtsuka,
  • Masato Ohtsuka,
  • Naoko Negishi,
  • Sonoko Habu,
  • Takehito Sato,
  • Katsuto Hozumi

DOI
https://doi.org/10.3389/fimmu.2022.852427
Journal volume & issue
Vol. 13

Abstract

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T-cell development in the thymus is dependent on Notch signaling induced by the interaction of Notch1, present on immigrant cells, with a Notch ligand, delta-like (Dll) 4, on the thymic epithelial cells. Phylogenetic analysis characterizing the properties of the Dll4 molecule suggests that Dll4 emerged from the common ancestor of lobe- and ray-finned fishes and diverged into bony fishes and terrestrial organisms, including mammals. The thymus evolved in cartilaginous fishes before Dll4, suggesting that T-cell development in cartilaginous fishes is dependent on Dll1 instead of Dll4. In this study, we compared the function of both Dll molecules in the thymic epithelium using Foxn1-cre and Dll4-floxed mice with conditional transgenic alleles in which the Dll1 or Dll4 gene is transcribed after the cre-mediated excision of the stop codon. The expression of Dll1 in the thymic epithelium completely restored the defect in the Dll4-deficient condition, suggesting that Dll1 can trigger Notch signaling that is indispensable for T-cell development in the thymus. Moreover, using bone marrow chimeras with Notch1- or Notch2-deficient hematopoietic cells, we showed that Dll1 is able to activate Notch signaling, which is sufficient to induce T-cell development, with both the receptors, in contrast to Dll4, which works only with Notch1, in the thymic environment. These results strongly support the hypothesis that Dll1 regulates T-cell development via Notch1 and/or Notch2 in the thymus of cartilaginous fishes and that Dll4 has replaced Dll1 in inducing thymic Notch signaling via Notch1 during evolution.

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