Use of dirty mice to study skin resident memory T cells in cancer treatments and graft-versus-host-disease

Abstract

Abstract Graft versus host disease (GVHD) is a significant cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). While donor T cells have been shown to be instrumental in disease pathogenesis, prior studies of host T cells are limited, as host T cells are assumed to be depleted by conditioning (chemotherapy ± irradiation) used in HSCT. Recent data suggest that host skin resident memory T cells survive HSCT conditioning in humans and contribute to GVHD, but deeper mechanistic interrogation is necessary. Herein, we developed a novel mouse model using dirty mice to study host skin resident memory T cells in chemotherapy and GVHD. Laboratory mice cohoused with pet-shop mice developed a robust memory T cell population including CD44high CD62Lhigh central memory T cells, CD44high CD62Llow effector memory T cells, and CD44high CD62Llow CD69+ CD103+ and CD103− skin resident memory T cells of both CD4+ and CD8+ T cell subsets. Similarly to human data, both CD4+ and CD8+ skin resident memory T cells in dirty mice survived induction chemotherapy and HSCT conditioning while other T cell populations in blood, lymph node and spleen were depleted. In a reduced intensity conditioning chemotherapy-based fully mismatched model of GVHD, dirty mice developed higher GVHD score than clean control mice, with some dirty mice developing early vitiliginous skin change that was not observed in clean controls. Taken together, dirty mice appear to be an ideal model to test skin resident memory T cells in cancer treatments and GVHD, and more broadly in inflammatory skin diseases. Supported by grants from Brigham Research Institute (126409)