MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function

Abstract

MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 T cells and conventional CD4 CD25 T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 donor T cells and promoting exhaustion in donor CD4 T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration.

MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

“…Lack of miR155 leads to the impairment of CD4 ؉ and CD8 ؉ T cell recruitment in the livers and spleens of L. donovani-infected mice. It is well known that miR155 deficiency leads to decreased trafficking of CD4 ϩ and CD8 ϩ T cells in various viral infections, like coronavirus (19) and herpes simplex encephalitis (20), as well as under other conditions, like acute graft-versus-host disease (21). It also has been shown that miR155 is highly expressed on regulatory T cells and is a direct target for Foxp3 (22).…”

PRMT5 regulates T cell interferon response and is a target for acute graft-versus-host disease

“…Individual mice were ear tagged and graded (on a scale from 0 to 8) twice a week. Mice who reached an aGVHD score of more than or equal to 7 were very sick and were euthanized and their tissues harvested (86,87). GVHD was also assessed by detailed histopathology analysis of H&E-stained liver and gut tissues using a previously reported scoring system with a range of 0 (absence of signs of GVHD) to 4 (maximal GVHD damage) (88).…”

Extracellular Vesicles After Allogeneic Hematopoietic Cell Transplantation: Emerging Role in Post-Transplant Complications

“…MiR155 upregulation has been observed in immune cells and in EVs in specimens from patients with evidence of intestinal GvHD (83) and in rodent GvHD experimental models (82). It has been shown that the dysregulation of miR155 in mouse model drives T H 1 proinflammatory T-cell phenotype (84). In this context, the infusion of EVs loaded with anti-miR155 in preclinical models reduced differentiation toward T H 1, T H 9, and T H 17 cells and skewed differentiation toward T H 2 and Treg cells, thus ameliorating the manifestations of GvHD and increasing mice survival (85).…”