miR-146a controls the resolution of T cell responses in mice.
T cell responses in mammals must be tightly regulated to both provide effective immune protection and avoid inflammation-induced pathology. NF-κB activation is a key signaling event induced by T cell receptor (TCR) stimulation. Dysregulation of NF-κB is associated with T cell-mediated inflammatory diseases and malignancies, highlighting the importance of negative feedback control of TCR-induced NF-κB activity. In this study we show that in mice, T cells lacking miR-146a are hyperactive in both acute antigenic responses and chronic inflammatory autoimmune responses. TCR-driven NF-κB activation up-regulates the expression of miR-146a, which in turn down-regulates NF-κB activity, at least partly through repressing the NF-κB signaling transducers TRAF6 and IRAK1. Thus, our results identify miR-146a as an important new member of the negative feedback loop that controls TCR signaling to NF-κB. Our findings also add microRNA to the list of regulators that control the resolution of T cell responses.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. liyang@caltech.edu
Lili
L
Yang
Mark P
MP
Boldin
Yang
Y
Yu
Claret Siyuan
CS
Liu
Chee-Kwee
CK
Ea
Parameswaran
P
Ramakrishnan
Konstantin D
KD
Taganov
Jimmy L
JL
Zhao
David
D
Baltimore
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
D000941:Antigens; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D048029:TNF Receptor-Associated Factor 6; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse