Depletion of host CCR7+ Dendritic Cells Prevented Donor T cell Tissue Tropism in Anti-CD3-Conditioned Recipients

摘要

We reported previously that anti-CD3 mAb treatment before HCT prevented graft versus host disease (GVHD) and preserved graft-versus-leukemia (GVL) effects in mice. These effects were associated with down-regulated donor T cell expression of tissue-specific homing and chemokine receptors, marked reduction of donor T cell migration into GVHD target tissues, and deletion of CD103⁺ dendritic cells (DCs) in mesenteric lymph nodes (MLN). MLN CD103⁺ DCs and peripheral lymph node (PLN) DCs include CCR7⁺ and CCR7⁻ subsets, but the role of these DC subsets in regulating donor T cell expression of homing and chemokine receptors remain unclear. Here, we show that recipient CCR7⁺ but not CCR7⁻ DCs in MLN induced donor T cell expression of gut-specific homing and chemokine receptors in a retinoid acid (RA)-dependent manner. CCR7 regulated activated DC migration from tissue to draining lymph node, but was not required for the ability of DCs to induce donor T cell expression of tissue-specific homing and chemokine receptors. Finally, anti-CD3 treatment depleted CCR7⁺ but not CCR7⁻ DCs by inducing sequential expansion and apoptosis of CCR7⁺ DCs in MLN and PLN. Apoptosis of CCR7⁺ DCs was associated with DC up-regulation of Fas expression and NK cell but not T, B or dendritic cell upregulation of FasL expression in the lymph nodes. These results suggest that depletion of CCR7⁺ host-type DCs with subsequent inhibition of donor T cell migration into GVHD target tissues can be an effective approach in prevention of acute GVHD and preservation of GVL effects (244).