Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity.
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.
Zhou
Xuyu
X
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Jeker
Lukas T
LT
Fife
Brian T
BT
Zhu
Shirley
S
Anderson
Mark S
MS
McManus
Michael T
MT
Bluestone
Jeffrey A
JA
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D002454:Cell Differentiation; D002469:Cell Separation; D022202:Chromosomes, Artificial, Bacterial; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics*; D005434:Flow Cytometry; D007107:Immune System; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D010641:Phenotype; D043244:Ribonuclease III; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*
D035683:MicroRNAs; D004722:Endoribonucleases; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases