Distinct clonal alloimmune T cell responses drive the human Graft Versus Leukaemia effect and Graft Versus Host Disease

The graft versus leukaemia effect (GVL) is the alloimmune therapeutic mechanism of allogeneic bone marrow transplantation (BMT), whilst acute graft versus host disease (GVHD) is unwanted alloimmune targeting of other tissues and is the main cause of non-relapse death. Both are T cell mediated and clinically correlate but can be separated - long term survival due to successful GVL occurs frequently in the absence of GVHD, and GVL failure occurs despite significant GVHD. I have constructed a large single cell RNA sequencing (scRNAseq) GVHD atlas of 490,943 cells mainly from epidermis, dermis and PBMC, and implicated specific T cell populations (CD4 cytotoxic lymphocytes) and homing mechanisms (CXCL9/10/11 amongst others). The purpose of this study is to apply scRNAseq for gene expression and antigen receptor profiling to GVL and GVHD simultaneously to test the hypothesis that they are separable by clonotype, spatial distribution and T cell phenotype. Using parallel sampling of skin, blood and bone marrow from the same individual at key time points (skin at GVHD onset, BM at D30 and D100) I will determine: 1) T cell clonotypes expanded in GVHD and GVL target organs (skin and BM) 2) Differential spatial distribution between skin (GVHD), bone marrow (GVL) and peripheral blood, and receptor ligand pairings driving tissue tropism 3) Differential regulation of phenotype and activation state of dominant T cell clones in GVHD and GVL target tissues through micro-environmental signals My long-term objective is to identify potential therapeutic targets to treat GVHD or augment GVL to improve BMT survival.