Abstract Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the preferred approach for the treatment of patients with malignant diseases of the bone marrow (BM) and congenital BM failure syndromes. The efficacy of allo-HSCT is dependent on the anti-tumor activity of the conditioning therapy and the donor graft. The efficacy of allo-HSCT is dependent on the ability of donor bone marrow/stem cells to replace the host immune system. However, it is clear that not all immune cells are generated from adult bone marrow cells. B1b lymphocytes and Langerhans cells are generated from fetal cells and not reconstituted by donor bone marrow. Additionally, our group and others have shown that innate lymphoid cells (ILC), which generate cytokines similar to T lymphocytes but don’t express germ-line encoded receptors, are not completely reconstituted after stem cell transplantation. The mechanism for the absence of ILC2 cells in the GI tract post allo-HSCT is not clear as these cells routinely are found in the bloodstream of patients and are reconstituted after autologous stem cell transplantation. Our group has found in mice that fetal liver derived ILC2 precursor cells can reconstitute the GI tract indicating that the niche can support ILC2 cells. This has led us to hypothesize that the inflammatory response found after allo-HSCT from the GvH response limits the development of ILC2 cells. ILC2 cells have significant plasticity, mediated by epigenetic changes in critical lineage-specific loci that leads to the development of ex-ILC2 cells, which are functionally similar to ILC1 or ILC3 cells. Our group has found that ILC1 cells, which generate IFN-γ, exacerbate GI tract GvHD. Furthermore, the pro-inflammatory cytokines, IL-12 and IL-1β, which are increased post allo-HSCT especially in the presence of the GvH response, convert ILC2 to ILC1 cells. Our group has found in ILC2 cells that H3K9me1/2 marks, which maintain gene transcription of gata3, cmaf and rora, critical for ILC2 maintenance and function, are enhanced by inhibiting lysine specific demethylases. The first specific aim focuses on enhancing the function of ILC2 cells in vivo to treat GvHD by inhibiting Jumonji containing and lysine-specific demethylases. Bronchiolitis obliterans syndrome (BOS) is a significant complication of allo-HSCT. T cells that generate IL- 17A, Th17 cells, are critical to the pathogenesis of BOS. One risk factor for BOS is an antecedent viral infection of the lung, although the mechanism for this is not clear. Quite recently our group has found that viral infection in the lung converts lung ILC2 cells to ILC3-like cells that generate IL-23 critical for the expansion of Th17 cells. The second specific aim of this proposal focuses on the use of demethylases given with ILC2 cells to prevent and/or treat post-viral BOS. Completion of the goals of this project will greatly enhance our understanding of the mechanisms important for the loss of ILC2 cells post-transplant,...