Spatial Multiomics Analysis Identifies SOCS1 as a Key Immune Checkpoint in T cell Tolerance Induction of HSCT

Abstract Achieving T cell tolerance ensures superior clinical outcomes in hematopoietic stem cell transplantation (HSCT). However, the in vivo T cell tolerance profiles in physiological state need to be further delineated. Here, we characterized the gene expression profile in tolerant T cells which was induced in healthy donors by granulocyte colony-stimulating factor, a stem cell mobilizer extensively used in HSCT. We identified suppressor of cytokine signaling 1 (SOCS1) as an essential immune checkpoint for T cell tolerance in the mouse models and primary T cells in the HSCT context. Further spatial multiomics analysis characterized the distinct three-dimensional genome architecture and the gene regulatory network in tolerant T cells. We found STAT3 competes with CTCF and mediates the formation of a new chromatin loop between the SOCS1 promoter and upstream super enhancers during the induction of T cell tolerance. This study identifies SOCS1 as a key immune checkpoint and potential immune target for improving outcome of patients with HSCT.