MicroRNA-155 modulates acute graft-versus-host disease by impacting T cell expansion, migration, and effector function

Nina C. Zitzer, Katiri Snyder, Xiamoei Meng, Patricia A. Taylor, Yvonne A. Efebera, Steven M. Devine, Bruce R. Blazar, Ramiro Garzon, Parvathi Ranganathan

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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 graftversushost 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-1552/2 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.

Original languageEnglish (US)
Pages (from-to)4170-4179
Number of pages10
JournalJournal of Immunology
Volume200
Issue number12
DOIs
StatePublished - Jun 15 2018

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants 1R21HL117707-01R01 (to Y.A.E. and R.G.), T32 5T32CA009338-37 (to N.C.Z.), HL56067, AI344965, and HL11879 (to B.R.B.), a Leukemia and Lymphoma Society Special Fellow Award (to P.R.), a Leukemia and Lymphoma Society Scholar Award (to R.G.), and an American Cancer Society Research Scholar Award (to R.G.).

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