Transcriptional profiling and single-cell chimerism analysis identifies human tissue resident T cells in the human skin after allogeneic stem cell transplantation

Abstract

Tissue resident memory T cells (TRM) 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 in loco unlike recirculating effector memory T cells (TEM). Insights into the maintenance and regulatory checkpoints of human tissue resident T cells (TRM) 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 bona fide 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,

Human resident memory T cells exit the skin and mediate systemic Th2-driven inflammation

“…We also found increased expression of protein-coding genes for fatty acid–binding protein 5 ( FABP5 ) and LGALS3 , as well as the transcription factors RUNX3 and PRDM1 ( Fig. 5 E ), all previously described in TRMs ( de Almeida et al, 2020 Preprint ; Milner et al, 2017 ; Pan et al, 2017 ; Strobl et al, 2020b ). The majority of cells in this cluster expressed genes encoding for the αβ-TCR ( Fig.…”

“…4 E ). Interestingly, we found host cells to have a gene expression profile relating to a cTRM phenotype, with a trend of higher expression of cTRM markers ITGAE (CD103), SELPLG (encoding for CLA), LGALS3 (encoding for Galectin-3), and PRDM1 , which have been associated with TRMs ( de Almeida et al, 2020 Preprint ; Mackay et al, 2016 ; Strobl et al, 2020b ). Host cells also displayed significantly higher levels of FABP5 , encoding for the fatty acid–binding protein 5 known to be crucial for skin TRM metabolism ( Pan et al, 2017 ).…”

Human skin-resident host T cells can persist long term after allogeneic stem cell transplantation and maintain recirculation potential

“…2C and Table 3B). This represents a proof of concept for the existence of a long-term bona fide skin-resident T cell subset (skin T RM ) (15).…”

Natural Barcodes for Longitudinal Single Cell Tracking of Leukemic and Immune Cell Dynamics

“…The strength of this approach is that no additional sequencing is needed and that it allows for annotation of even rare cells through a simple but robust analysis. Examples include tracking of circulating host tissue-resident T cells following myeloablative conditioning ( 122 ) or donor-derived immune cells following solid organ transplant ( 123 ). A limitation is that sex mismatch only occurs in a subset of transplants.…”

“…Lineage-tracing approaches have the potential to deepen the understanding of GvHD by dissecting the contribution of donor and recipient-derived T cells to GvHD target organs. An example of this approach demonstrated that tissue-resident memory T cells can retain a large fraction of host cells despite full systemic chimerism ( 122 ).…”