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Excessive expression of miR-27 impairs Treg-mediated immunological tolerance
Leilani O. Cruz, … , Aly Azeem Khan, Li-Fan Lu
Leilani O. Cruz, … , Aly Azeem Khan, Li-Fan Lu
Published January 9, 2017
Citation Information: J Clin Invest. 2017;127(2):530-542. https://doi.org/10.1172/JCI88415.
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Research Article Autoimmunity Immunology

Excessive expression of miR-27 impairs Treg-mediated immunological tolerance

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Abstract

MicroRNAs (miRs) are tightly regulated in the immune system, and aberrant expression of miRs often results in hematopoietic malignancies and autoimmune diseases. Previously, it was suggested that elevated levels of miR-27 in T cells isolated from patients with multiple sclerosis facilitate disease progression by inhibiting Th2 immunity and promoting pathogenic Th1 responses. Here we have demonstrated that, although mice with T cell–specific overexpression of miR-27 harbor dysregulated Th1 responses and develop autoimmune pathology, these disease phenotypes are not driven by miR-27 in effector T cells in a cell-autonomous manner. Rather, dysregulation of Th1 responses and autoimmunity resulted from a perturbed Treg compartment. Excessive miR-27 expression in murine T cells severely impaired Treg differentiation. Moreover, Tregs with exaggerated miR-27–mediated gene regulation exhibited diminished homeostasis and suppressor function in vivo. Mechanistically, we determined that miR-27 represses several known as well as previously uncharacterized targets that play critical roles in controlling multiple aspects of Treg biology. Collectively, our data show that miR-27 functions as a key regulator in Treg development and function and suggest that proper regulation of miR-27 is pivotal to safeguarding Treg-mediated immunological tolerance.

Authors

Leilani O. Cruz, Somaye Sadat Hashemifar, Cheng-Jang Wu, Sunglim Cho, Duc T. Nguyen, Ling-Li Lin, Aly Azeem Khan, Li-Fan Lu

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Figure 1

Diminished IFN-γ production by miR-27–overexpressing T cells in CD4-Cre R27Tg mice.

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Diminished IFN-γ production by miR-27–overexpressing T cells in CD4-Cre ...
(A) FACS analysis of IFN-γ+ cells in FOXP3–CD4+ Tconvs from mice of different ages (>14 wk vs. ~5 wk). (B) Frequencies and (C) mean fluorescence intensity (MFI) of IFN-γ in R27Tg Tconvs compared with WT Tconvs from mice older than 14 weeks. Data represent the mean ± SD and are representative of 3 independent experiments. Each symbol represents an individual mouse, and the bar represents the mean. *P < 0.05. P values are determined by an unpaired, 2-tailed Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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