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Mature T cell responses are controlled by microRNA-142
Yaping Sun, … , Thomas Saunders, Pavan Reddy
Yaping Sun, … , Thomas Saunders, Pavan Reddy
Published June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2825-2840. https://doi.org/10.1172/JCI78753.
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Research Article Immunology Article has an altmetric score of 9

Mature T cell responses are controlled by microRNA-142

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Abstract

T cell proliferation is critical for immune responses; however, the molecular mechanisms that mediate the proliferative response are poorly understood. MicroRNAs (miRs) regulate various molecular processes, including development and function of the immune system. Here, utilizing multiple complementary genetic and molecular approaches, we investigated the contribution of a hematopoietic-specific miR, miR-142, in regulating T cell responses. T cell development was not affected in animals with a targeted deletion of Mir142; however, T cell proliferation was markedly reduced following stimulation both in vitro and in multiple murine models of graft-versus-host disease (GVHD). miR-142–deficient T cells demonstrated substantial cell-cycling defects, and microarray and bioinformatics analyses revealed upregulation of genes involved in cell cycling. Moreover, 2 predicted miR-142 target genes, the atypical E2F transcription factors E2f7 and E2f8, were most highly upregulated in miR-142–deficient cells. Clustered regularly interspaced short palindromic repeat interference–mediated (CRISPRi-mediated) silencing of E2F7 and E2F8 in miR-142–deficient T cells ameliorated cell-cycling defects and reduced GVHD, and overexpression of these factors in WT T cells inhibited the proliferative response. Together, these results identify a link between hematopoietic-specific miR-142 and atypical E2F transcription factors in the regulation of mature T cell cycling and suggest that targeting this interaction may be relevant for mitigating GVHD.

Authors

Yaping Sun, Katherine Oravecz-Wilson, Nathan Mathewson, Ying Wang, Richard McEachin, Chen Liu, Tomomi Toubai, Julia Wu, Corinne Rossi, Thomas Braun, Thomas Saunders, Pavan Reddy

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Figure 6

Atypical E2F proteins were significantly upregulated in miR-142 KO T cells.

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Atypical E2F proteins were significantly upregulated in miR-142 KO T cel...
(A) Confirming upregulated E2f7 and E2f8 in miR-142 KO T cells using qPCR. Combined results (mean ± SEM) were from 3 independent experiments as shown in Supplemental Figure 10A. P values were obtained using the unpaired t test. (B) Western blotting demonstrated that E2F7 and E2F8 were upregulated in miR-142 KO T cells. Data are representative of 3 independent experiments. (C) Confirming upregulated E2F7 and E2F8 in miR-142 KO T cells using ICC. Purified T cells from either miR-142 KO or WT mice were spread onto polylysine-precoated slides by cytocentrifugation and processed for ICC with specific Abs against E2F7 and E2F8. Dark brown staining in cytoplasm was observed, as indicated by arrows. Much stronger (darker brown) staining was observed in miR-142 KO T cells, as indicated by arrowheads. Data are representative of 3 similar experiments. Original magnification, ×400. (D) Significantly increased expression of E2F7 and E2F8 in response to anti-CD3 and anti-CD28 Ab stimulation. Dynamic observation of expression of E2F7 and E2F8 in response to in vitro stimulation with anti-CD3 and anti-CD28 Abs was conducted for 0–48 hours. Data represent combination of 3 independent experiments (mean ± SEM). P values were obtained using multiple t test. *P < 0.05; **P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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