The Journal of Experimental Medicine
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Published online 11 July 2005 doi:10.1084/jem.20050678
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 2, 261-269
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ARTICLE

 Aberrant T cell differentiation in the absence of Dicer

Stefan A. Muljo1, K. Mark Ansel1, Chryssa Kanellopoulou2, David M. Livingston2, Anjana Rao1, and Klaus Rajewsky1

1 The CBR Institute for Biomedical Research and Department of Pathology, Department of Cancer Biology, Harvard Medical School, Boston, MA 02115
2 The Dana-Farber Cancer Institute, Department of Cancer Biology, Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Klaus Rajewsky: rajewsky{at}cbr.med.harvard.edu

Dicer is an RNaseIII-like enzyme that is required for generating short interfering RNAs and microRNAs. The latter have been implicated in regulating cell fate determination in invertebrates and vertebrates. To test the requirement for Dicer in cell-lineage decisions in a mammalian organism, we have generated a conditional allele of dicer-1 (dcr-1) in the mouse. Specific deletion of dcr-1 in the T cell lineage resulted in impaired T cell development and aberrant T helper cell differentiation and cytokine production. A severe block in peripheral CD8+ T cell development was observed upon dcr-1 deletion in the thymus. However, Dicer-deficient CD4+ T cells, although reduced in numbers, were viable and could be analyzed further. These cells were defective in microRNA processing, and upon stimulation they proliferated poorly and underwent increased apoptosis. Independent of their proliferation defect, Dicer-deficient helper T cells preferentially expressed interferon-{gamma}, the hallmark effector cytokine of the Th1 lineage.

Abbreviations used: CD4cre, Cre transgene under the control of the cd4 enhancer/promoter/silencer; CFSE, carboxyfluorescein diacetate succinimidyl ester; dcr-1, dicer-1; DN, double-negative; DP, double-positive; ES, embryonic stem; floxed, loxP-flanked; miRNA, microRNA; PI, propidium iodide; pre-miRNA, precursor microRNA; RNAi, RNA interference; siRNA, short interfering RNA; SP, single positive; YFP, yellow fluorescent protein.

S.A. Muljo, K.M. Ansel, and C. Kanellopoulou contributed equally to this work.


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