Graft-Versus-Host Disease Leads to Systemic Elimination of Innate Lymphoid Cells and Abolishes Their Development

Abstract

Innate lymphoid cells (ILCs) are associated with protective mucosal response after experimental allogeneic BMT. However, the specific in vivo roles of ILCs and their capacity for reconstitution post-transplant remain unclear. We therefore sought to characterize the significance and tissue distribution of ILCs after allo-BMT. To study the role of ILCs after allo-BMT, we established a clinically relevant acute GVHD model based on H-Y antigen mismatch. Lethally irradiated Rag2−/− male mice (Thy1.2, B6) were transplanted with T cell depleted (TCD) bone marrow and purified T cells obtained from wild-type female mice (Thy1.1, B6). To deplete host-derived ILCs, recipient mice were treated with an anti-Thy1.2 antibody or an anti-isotype antibody prior to BMT. Pre-transplant depletion of ILCs induced significantly worse systemic signs of GVHD, as well as increased thymic injury and intestinal GVHD pathology, indicating an important role for ILCs after BMT (Fig. 1). To better understand the systemic roles of ILCs, we evaluated ILC subsets in the intestine, liver, and lungs after allo-BMT. Two weeks after MHC-mismatched (C57BL6 into BALB/c) TCD-BMT, both donor- and host-derived ILCs could be detected in all tissues. Liver was characterized by a high number of NK cells and ILC1s, while the lungs contained a high proportion of ILC2s, and small intestine contained relatively greater ILC3s. For all tissues analyzed, the majority of ILCs were host-derived. During T cell replete BMT resulting in GVHD, both donor and host-derived ILCs were significantly reduced in all tissues compared to TCD-BMT mice (Fig. 2). To better understand the loss of donor-derived ILCs caused by donor T cells, we investigated ILC precursors in recipient marrow post-BMT, and found a significant loss of CLPs, αLPs, CHILPs, and ILC2 precursors in mice with GVHD. These data suggested that bone marrow involvement with GVHD induced a loss of ILC precursors impairing their reconstitution post-BMT. Given the loss of ILCs occurring post-BMT and the increased GVHD severity in BMT recipients lacking ILCs, we hypothesized that expansion of the ILC compartment pre-transplant could help protect BMT recipients from GVHD. Aryl hydrocarbon receptor (AhR) signaling has been associated with ILC3 development and maintenance during intestinal homeostasis. We thus evaluated the effect of diet-derived AhR ligands (AhRL) on intestinal ILCs and BMT outcomes. Prior to transplantation, mice were given diets containing or lacking AhRL. Mice on an AhRL-poor diet showed reduced intestinal ILC3s, increased intestinal GVHD pathology, and increased mortality post-BMT. In conclusion, ILCs contribute to tissue protection following allo-BMT, but GVHD leads to elimination of pre-existing ILCs and abolishes their development. Dietary supplementation with AhRL-rich foods may represent an approach to enhance mucosal immunity and intestinal recovery post-BMT.