miR-181a is an intrinsic modulator of T cell sensitivity and selection.
T cell sensitivity to antigen is intrinsically regulated during maturation to ensure proper development of immunity and tolerance, but how this is accomplished remains elusive. Here we show that increasing miR-181a expression in mature T cells augments the sensitivity to peptide antigens, while inhibiting miR-181a expression in the immature T cells reduces sensitivity and impairs both positive and negative selection. Moreover, quantitative regulation of T cell sensitivity by miR-181a enables mature T cells to recognize antagonists-the inhibitory peptide antigens-as agonists. These effects are in part achieved by the downregulation of multiple phosphatases, which leads to elevated steady-state levels of phosphorylated intermediates and a reduction of the T cell receptor signaling threshold. Importantly, higher miR-181a expression correlates with greater T cell sensitivity in immature T cells, suggesting that miR-181a acts as an intrinsic antigen sensitivity "rheostat" during T cell development.
Li
Qi-Jing
QJ
Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chau
Jacqueline
J
Ebert
Peter J R
PJ
Sylvester
Giselle
G
Min
Hyeyoung
H
Liu
Gwen
G
Braich
Ravi
R
Manoharan
Muthiah
M
Soutschek
Juergen
J
Skare
Petra
P
Klein
Lawrence O
LO
Davis
Mark M
MM
Chen
Chang-Zheng
CZ
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000737:chemistry / Q000276:immunology; D015536:Down-Regulation; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009036:Moths; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010455:Peptides / Q000276:immunology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D045304:Cytochromes c; D010744:Phosphoric Monoester Hydrolases