Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo

Koichiro Abe, Felix O. Yarovinsky, Takaya Murakami, Alexander N. Shakhov, Alexei V. Tumanov, Daisuke Ito, Ludmila N. Drutskaya, Klaus Pfeffer, Dmitry V. Kuprash, Kristin L. Komschlies, Sergei A. Nedospasov

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

TNF/LTα/LTβ (tumor necrosis factor/lymphotoxin-α/lymphotoxin-β) triple knockout (KO) mice show a significant reduction of dendritic cell (DC) number in the spleen, presumably due to defective recruitment and/or production. To distinguish between these possibilities, DCs were generated from bone marrow (BM) cultures prepared from wild-type (wt) and mutant mice in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The yield of CD11c+ major histocompatibility complex (MHC) class II+ DCs generated from TNF/LTα/LTβ-/- BM culture was significantly reduced compared with wt BM culture. In order to further dissect the individual pathways responsible for defective DC properties observed in TNF/LTα/LTβ-/- mice, the panel of TNF/LT ligand and receptor single KO mice were used. The production of DCs from BM culture was significantly reduced in TNF-/- and TNF receptor (TNFR) p55-/- mice, but normal in LTα-/-, LTβ-/-, LTβR-/- mice. Recombinant TNF (rTNF) exogenously added to TNF/LTα/LTβ-/- BM cultures could reverse this defect, and blocking antibodies showed partial effect on BM cultures of wt mice. Conversely, numbers of mature DCs in spleen were significantly decreased in LTα-/-, LTβ-/-, LTβR-/- mice, but not in TNF-/- and TNFRp55-/- mice. These results reveal 2 distinct contributions of TNF/LT cytokines. First, TNF acting through TNF receptor is involved in the development/maturation of DCs in BM progenitor cultures, but this function appears to be redundant in vivo. Second, the microenvironment in peripheral lymphoid organs associated with LTα/LTβ-LTβR signaling and chemokine production is critical for recruitment efficiency of DCs, and this pathway is indispensable.

Original languageEnglish (US)
Pages (from-to)1477-1483
Number of pages7
JournalBlood
Volume101
Issue number4
DOIs
StatePublished - Feb 15 2003

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Abe, K., Yarovinsky, F. O., Murakami, T., Shakhov, A. N., Tumanov, A. V., Ito, D., Drutskaya, L. N., Pfeffer, K., Kuprash, D. V., Komschlies, K. L., & Nedospasov, S. A. (2003). Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo. Blood, 101(4), 1477-1483. https://doi.org/10.1182/blood.V101.4.1477