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

Publication Type:

Journal Article

Source:

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2014)

Keywords:

2014, April 2014, Clinical Research Division

Abstract:

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).