Figure 6.
Figure 6. TSP-1, by itself, enhances apoptotic monocyte engulfment by iDCs, and inhibits iDC maturation and T-cell activation. (A) Proposed mechanisms of TSP-1's effect on iDCs. (Ai) TSP-1 structural and functional domains that are relevant to apoptotic cell clearance. The relevant interacting receptors for each domain are indicated. HBD indicates heparin binding domain. (Aii) Mechanisms of TSP-1 as a bridging molecule. TSP-1 may be expressed by phagocytes (Aii, left) or by apoptotic cells (Aii, middle) that also can secrete the N-terminal domain. Whether the source is the engulfing cell or the apoptotic cell, TSP-1 or the N-terminal domain serves as a bridge between apoptotic cells and phagocytes (Aii, right). (Aiii)Alternatively (no bridge), TSP-1 or the N-terminal domain may bind to iDCs and induce ameliorated phagocytosis and immune suppression, even in the absence of attached apoptotic cells. (B) TSP-1 enhances latex bead engulfment by iDCs. Green fluorescent latex beads were offered to iDCs at a 16:1 ratio, in the presence or absence of 2 μg/mLTSP-1. The gray-filled curve represents iDCs that were not exposed to green fluorescent latex beads. Of the TSP-1-treated iDCs, 22.6% ± 0.1% engulfed at least 1 latex bead, compared with 15.6% ± 1.8% in the absence of TSP-1, indicating approximately 45% augmentation of phagocytic capacity following TSP-1 exposure (P < .001). Data are representative of 3 experiments. (C) TSP-1 inhibits iDC maturation. iDCs were treated with 5 ng/mL LPS in the absence or presence of 1 μg/mL TSP-1, or remained untreated. Mean fluorescence decreased from 453 to 283 (38%, P < .001, representative of 3 experiments) for DR and from 53 to 21 (39%, P < .001, representative of 3 experiments) for CD86. The bright-filled curve represents isotype control. (D) TSP-1 inhibits T-cell activation. CFSE-labeled T cells were cocultured in different ratios with LPS-treated DCs (left) or DCs that were exposed to TSP1 for 5 hours before LPS treatment (right). Exposure to TSP1 prior to LPS treatment inhibited DC-induced T-cell activation by 27% at 2:1 T-cell/DC ratio and by 50% at 4:1 T-cell/DC ratio.

TSP-1, by itself, enhances apoptotic monocyte engulfment by iDCs, and inhibits iDC maturation and T-cell activation. (A) Proposed mechanisms of TSP-1's effect on iDCs. (Ai) TSP-1 structural and functional domains that are relevant to apoptotic cell clearance. The relevant interacting receptors for each domain are indicated. HBD indicates heparin binding domain. (Aii) Mechanisms of TSP-1 as a bridging molecule. TSP-1 may be expressed by phagocytes (Aii, left) or by apoptotic cells (Aii, middle) that also can secrete the N-terminal domain. Whether the source is the engulfing cell or the apoptotic cell, TSP-1 or the N-terminal domain serves as a bridge between apoptotic cells and phagocytes (Aii, right). (Aiii)Alternatively (no bridge), TSP-1 or the N-terminal domain may bind to iDCs and induce ameliorated phagocytosis and immune suppression, even in the absence of attached apoptotic cells. (B) TSP-1 enhances latex bead engulfment by iDCs. Green fluorescent latex beads were offered to iDCs at a 16:1 ratio, in the presence or absence of 2 μg/mLTSP-1. The gray-filled curve represents iDCs that were not exposed to green fluorescent latex beads. Of the TSP-1-treated iDCs, 22.6% ± 0.1% engulfed at least 1 latex bead, compared with 15.6% ± 1.8% in the absence of TSP-1, indicating approximately 45% augmentation of phagocytic capacity following TSP-1 exposure (P < .001). Data are representative of 3 experiments. (C) TSP-1 inhibits iDC maturation. iDCs were treated with 5 ng/mL LPS in the absence or presence of 1 μg/mL TSP-1, or remained untreated. Mean fluorescence decreased from 453 to 283 (38%, P < .001, representative of 3 experiments) for DR and from 53 to 21 (39%, P < .001, representative of 3 experiments) for CD86. The bright-filled curve represents isotype control. (D) TSP-1 inhibits T-cell activation. CFSE-labeled T cells were cocultured in different ratios with LPS-treated DCs (left) or DCs that were exposed to TSP1 for 5 hours before LPS treatment (right). Exposure to TSP1 prior to LPS treatment inhibited DC-induced T-cell activation by 27% at 2:1 T-cell/DC ratio and by 50% at 4:1 T-cell/DC ratio.

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