Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity.


Publication Type:

Journal Article

Source:

J Exp Med, Volume 205, Issue 9, p.1983-91 (2008)

Keywords:

Animals, Autoimmunity, Cell Differentiation, Cell Separation, Chromosomes, Artificial, Bacterial, DEAD-box RNA Helicases, Endoribonucleases, Flow Cytometry, Immune System, Lymphocyte Activation, Mice, Mice, Knockout, Mice, Transgenic, MicroRNAs, Phenotype, Ribonuclease III, T-Lymphocytes, Regulatory

Abstract:

<p>A new regulatory T (T reg) cell-specific, FoxP3-GFP-hCre bacterial artificial chromosome transgenic mouse was crossed to a conditional Dicer knockout (KO) mouse strain to analyze the role of microRNAs (miRNAs) in the development and function of T reg cells. Although thymic T reg cells developed normally in this setting, the cells showed evidence of altered differentiation and dysfunction in the periphery. Dicer-deficient T reg lineage cells failed to remain stable, as a subset of cells down-regulated the T reg cell-specific transcription factor FoxP3, whereas the majority expressed altered levels of multiple genes and proteins (including Neuropilin 1, glucocorticoid-induced tumor necrosis factor receptor, and cytotoxic T lymphocyte antigen 4) associated with the T reg cell fingerprint. In fact, a significant percentage of the T reg lineage cells took on a T helper cell memory phenotype including increased levels of CD127, interleukin 4, and interferon gamma. Importantly, Dicer-deficient T reg cells lost suppression activity in vivo; the mice rapidly developed fatal systemic autoimmune disease resembling the FoxP3 KO phenotype. These results support a central role for miRNAs in maintaining the stability of differentiated T reg cell function in vivo and homeostasis of the adaptive immune system.</p>