Multiomic Single Cell Evaluation Reveals Inflammatory Cytokines Affect Innate Lymphoid Cell Fate After Allogeneic Stem Cell Transplantation [ChIP-Seq]
Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. Previous work has shown that in mice and humans, ILC2s fail to reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating chromatin and transcriptomic analysis of marked, transplanted ILC2s at the single cell level, we identify a previously unreported population of converted ILC1-like cells in the small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines in vitro results in a mixed ILC1-ILC2 phenotype but was able to convert only an extremely small population of ILC2s to ILC1s as observed in vivo. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated-morbidity and mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Finally, circulating peripheral blood mononuclear cells from patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate, for the first time, that ILC2s fail to repopulate their protective niche after allo-HSCT in part due to conversion to a pro-pathogenic population marked by an ILC1-like chromatin state, providing novel insights into the contribution of ILC plasticity to aGvHD pathogenesis after allo-HSCT. Overall design: Following 4 days of in vivo administration of 0.4 ug IL-25, C57BL/6 mice were sacrificed and lineage (CD8a [clone 53-6.7], CD4 [RM 4.4], CD3e [145-2C11], ?dTCR [UC7-13DS], TER119 [TER-119], B220 [RA3-6B2], CD11b [M1/70], NK1.1 [PK136], CD11c [N418], CD19 [MB19-1], Ly6G [1A8], and CD49b [DX5]) negative, ST2+ cells from the peritoneum and mesenteric lymph nodes were isolated and expanded in culture for 6 days in the presence of recombinant IL-7 and IL-33 (ILC2).