Single-cell chimerism analysis and transcriptional profiling identify long-term human tissue-resident host T cells in the skin after allogeneic stem cell transplantation

Tissue resident memory T cells (T) have recently emerged as crucial cellular players for host defense in a wide variety of tissues and barrier sites. Mouse models revealed that they are maintained long-term unlike recirculating effector memory T cells (T). Insights into the maintenance and regulatory checkpoints of human tissue resident T cells (T) remain scarce, especially due to the obstacles in tracking T cells over time and system-wide in humans. We present a clinical model that allowed us to overcome these limitations. We demonstrate that allogeneic stem cell transplantation resulted in compartmentalization of host T cells in the human skin despite complete donor T cell chimerism in the blood, thus unmasking long-term persistence of tissue resident T cell subsets of host origin within the diverse skin T cell community. Single-cell transcriptional profiling paired with single-cell chimerism analysis provided an in-depth characterization of these skin resident T cells. Their phenotype, functions and regulatory checkpoints may serve therapeutic strategies for the treatment of autoimmune diseases and chronic infections, where their specific depletion versus maintenance, respectively, will have to be harnessed pharmaceutically.