Long-term skin-resident memory T cells proliferate in situ and are involved in human graft-versus-host disease

Abstract

The skin contains a population of tissue-resident memory T cells (Trm) that is thought to contribute to local tissue homeostasis and protection against environmental injuries. Although information about the regulation, survival program, and pathophysiological roles of Trm has been obtained from murine studies, little is known about the biology of human cutaneous Trm. Here, we showed that host-derived CD69+ αβ memory T cell clones in the epidermis and dermis remain stable and functionally competent for at least 10 years in patients with allogeneic hematopoietic stem cell transplantation. Single-cell RNA sequencing revealed low expression of genes encoding tissue egress molecules by long-term persisting Trm in the skin, whereas tissue retention molecules and stem cell markers were displayed by Trm. The transcription factor RUNX3 and the surface molecule galectin-3 were preferentially expressed by host T cells at the RNA and protein levels, suggesting two new markers for human skin Trm. Furthermore, skin lesions from patients developing graft-versus-host disease (GVHD) showed a large number of cytokine-producing host-derived Trm, suggesting a contribution of these cells to the pathogenesis of GVHD. Together, our studies highlighted the relationship between the local human skin environment and long-term persisting Trm, which differs from murine skin. Our results also indicated that local tissue inflammation occurs through host-derived Trm after allogeneic hematopoietic stem cell transplantation.

Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program

“…As hypoxia and TGF-β are common features of the tumor microenvironment (TME), our results suggest they may contribute to CD103 + TIL generation in vivo. Additionally, our results may help explain recent observations that TIL RM are more radioresistant, as hypoxia and TGF-β are known to contribute to radioresistance, and DEGs in radioresistant human skin T RM show enrichment in the hypoxia pathway, relative to tissue-infiltrating T cells ( 40 , 46 – 48 ).…”

“…Importantly, NR3C1 has previously been shown to promote the formation of memory precursor T cells and can be upregulated by hypoxia ( 38 , 39 ). In addition, there was considerable overlap between the transcriptional profiles of our i-T RM and human skin T RM , including a number of canonical hypoxia-responsive genes (e.g., LDHA , MMP9 , CA9 ), as well as LGALS3 , a newly identified marker of human skin T RM ( 40 ).…”

T Cell Subsets in Graft Versus Host Disease and Graft Versus Tumor

“…Pretransplant conditioning which typically consists of chemoimmunotherapeutic drugs and/or total body irradiation were thought to eliminate host T cells and therefore not play a role in GVHD, but new studies indicate that host T cells resident in peripheral tissues are highly resistant to depletion, even after high-intensity conditioning (109). In humans, host-derived Trm cells have been found in patients' skin lesions before and after allo-HCT and showed distinct transcriptomic program with RUNX3 and galectin-3 as the phenotypic signatures for these cells as compared to blood T cells (110). Similarly, host T cells were found in all skin and colon from patients with aGVHD after allo-HCT.…”

Single-Cell TCR and Transcriptome Analysis: An Indispensable Tool for Studying T-Cell Biology and Cancer Immunotherapy

“…Human IL-26 could attenuate immune responses in a mouse model of acute colitis. Next, Strobl J et al used single-cell technique to study tissue-resident memory T cells in skin, and they identified RUNX3 and LGALS3 as new markers for this type of T cells (74). They also identified a large number of host-derived tissue-resident memory T cells in skin lesions from patients developing graft-versus-host disease, suggesting the potential contribution of these cells to this disease.…”