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

Abstract

Emigration of tissue-resident memory T cells (TRMs) was recently introduced in mouse models and may drive systemic inflammation. Skin TRMs of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) can coexist beside donor T cells, offering a unique human model system to study T cell migration. By genotyping, mathematical modeling, single-cell transcriptomics, and functional analysis of patient blood and skin T cells, we detected a small consistent population of circulating skin-derived T cells with a TRM phenotype (cTRMs) in the blood and unveil their skin origin and striking resemblance to skin TRMs. Blood from patients with active graft-versus-host disease (GVHD) contains elevated numbers of host cTRMs producing pro-inflammatory Th2/Th17 cytokines and mediating keratinocyte damage. Expression of gut-homing receptors and the occurrence of cTRMs in gastrointestinal GVHD lesions emphasize their potential to reseed and propagate inflammation in distant organs. Collectively, we describe a distinct circulating T cell population mirroring skin inflammation, which could serve as a biomarker or therapeutic target in GVHD.

Processing human skin samples for single-cell assays

“…This protocol is superior to the one based on Collagenase IV/DNAse mixture for skin digestion often used in the literature ( Strobl et al., 2021 ) ( Figure 4 A). We do not separate epidermis from dermis in this protocol, as we do not specifically focus on one compartment.…”

Emerging Concepts of Tissue-resident Memory T Cells in Transplantation

“…Single cell RNA sequencing confirmed a TRM gene expression pattern of these recipient-derived cTRMs and they were demonstrated to be able to exert damage to keratinocytes in skin and home to distant tissue sites during GVHD, including the gastrointestinal tract, as they expressed the gut-homing marker integrin α4β7. 72…”

Perinatal derivatives: How to best validate their immunomodulatory functions

“…Many degenerative and acute diseases including GvHD, ischemic stroke, sepsis and COVID-19 are accompanied by uncontrolled pro-inflammatory reactions, regularly also involving T cell effector responses ( Hill 2009 ; Nakamura et al, 2020 ). Upon administration of potent PnD or adult MSC products that promote regeneration or improvement of acute disease symptoms, respectively, pathology associated T cell effector responses get suppressed in vivo and frequently are converted into regulatory T cell responses ( Balza et al, 2016 ; De Biasi et al, 2021 ; Strobl et al, 2021 ). Furthermore, perinatal and adult MSC products can convey immunomodulatory activities in different autoimmune disease models, highlight their ability to reduce Th1/Th17 imbalances and to trigger T cell polarization towards regulatory T cell functions ( Sun et al, 2009 ; Obermajer et al, 2014 ; Parolini et al, 2014 ; Tsai et al, 2014 ; Wang D et al, 2014 ; Wang H et al, 2014 ; Wang et al, 2017 ; Ma et al, 2019 ).…”