Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen

Kohei Fujita, Svetoslav Chakarov, Tetsuro Kobayashi, Keiko Sakamoto, Benjamin Voisin, Kaibo Duan, Taneaki Nakagawa, Keisuke Horiuchi, Masayuki Amagai, Florent Ginhoux, Keisuke Nagao

Research output: Contribution to journalArticle

Abstract

Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α+/CD103+ cDC1s and CD11b+ cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs (Itgax-cre × Adam10-fl/fl; ADAM10ΔDC) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10ΔDC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10ΔDC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival.

Original languageEnglish
Pages (from-to)14714-14723
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number29
DOIs
Publication statusPublished - 2019 Jan 1

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Dendritic Cells
Spleen
Bone Marrow
Disintegrins
Metalloproteases
Fibroblasts
Cytokines
Membranes
Serum

Keywords

  • ADAM10
  • Dendritic cells
  • Immunology

ASJC Scopus subject areas

  • General

Cite this

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen. / Fujita, Kohei; Chakarov, Svetoslav; Kobayashi, Tetsuro; Sakamoto, Keiko; Voisin, Benjamin; Duan, Kaibo; Nakagawa, Taneaki; Horiuchi, Keisuke; Amagai, Masayuki; Ginhoux, Florent; Nagao, Keisuke.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 29, 01.01.2019, p. 14714-14723.

Research output: Contribution to journalArticle

Fujita, Kohei ; Chakarov, Svetoslav ; Kobayashi, Tetsuro ; Sakamoto, Keiko ; Voisin, Benjamin ; Duan, Kaibo ; Nakagawa, Taneaki ; Horiuchi, Keisuke ; Amagai, Masayuki ; Ginhoux, Florent ; Nagao, Keisuke. / Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 29. pp. 14714-14723.
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AU - Voisin, Benjamin

AU - Duan, Kaibo

AU - Nakagawa, Taneaki

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AU - Nagao, Keisuke

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