Role of autoreactivity in pathogenesis of chronic graft versus host disease

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for patients with hematological malignancies (i.e. leukemia and lymphoma), through graft versus leukemia/lymphoma (GVL) effect mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) caused by the same alloreactive T cells remains a major obstacle. Chronic GVHD (cGVHD), a systemic autoimmune-like syndrome, remains a major cause of morbidity and mortality in long-term survivors of Allo-HCT. During the past decade, we have used murine and humanized murine models of cGVHD and biospecimens from cGVHD patients to demonstrate that CD4+ T cells and B cells and their interactions in GVHD target tissues such as the liver, lung and skin play a critical role in the pathogenesis and persistence of the disease. The premise of this new proposal is that deeper mechanistic understanding of the interactions between non-circulating tissue- resident CD4+ memory T (Trm) and tissue-resident B (Brm) cells in GVHD target tissues will identify new therapeutic targets for prevention or treatment of cGVHD. In Aim 1, we will determine whether CD4+ Trm cells initiate formation of tertiary lymphoid structures (TLS) in GVHD target tissues, in which Ly108+ stem cell-like progenitors maintain the pool of Trm and Brm to perpetuate cGVHD pathogenesis. We will also develop novel cell-penetrating PS-Cas9-gRNA to target STAT3 in donor T cells to prevent development of pathogenic CD4+ Trm and cGVHD while preserving GVL activity, because our recent studies indicate that STAT3 is required for Trm development. In Aim 2, we will determine whether B cell helper PD-1hiPSGL1loCD4+ Trh cells interact with T-bet+ Brm cells to produce autoantibodies that augment systemic tissue damage. In Aim 3, we will determine whether non-B cell helper PSGL1hiCD4+ Trm cells interact with dendritic cells, macrophages, and fibroblasts in cGVHD target tissues to mediate damage and fibrosis in an IL-33/ST2 pathway-dependent manner. These studies have high biological and translational significance and may lead to a paradigm shift in our understanding of cGVHD pathogenesis and to development of novel approaches for preventing and treating cGVHD.