TY - JOUR
T1 - Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo
AU - Abe, Koichiro
AU - Yarovinsky, Felix O.
AU - Murakami, Takaya
AU - Shakhov, Alexander N.
AU - Tumanov, Alexei V.
AU - Ito, Daisuke
AU - Drutskaya, Ludmila N.
AU - Pfeffer, Klaus
AU - Kuprash, Dmitry V.
AU - Komschlies, Kristin L.
AU - Nedospasov, Sergei A.
PY - 2003/2/15
Y1 - 2003/2/15
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.V101.4.1477
DO - 10.1182/blood.V101.4.1477
M3 - Article
C2 - 12560241
AN - SCOPUS:0037441879
SN - 0006-4971
VL - 101
SP - 1477
EP - 1483
JO - Blood
JF - Blood
IS - 4
ER -