301. miR-181a is an intrinsic modulator of T cell sensitivity and selection.
- Author
-
Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, Liu G, Braich R, Manoharan M, Soutschek J, Skare P, Klein LO, Davis MM, and Chen CZ
- Subjects
- Animals, Antigen-Presenting Cells immunology, Cell Differentiation, Cell Line, Tumor, Cytochromes c chemistry, Cytochromes c immunology, Down-Regulation, Gene Expression Regulation, Mice, Mice, Transgenic, MicroRNAs genetics, Moths, NIH 3T3 Cells, Oligonucleotides, Antisense genetics, Oligonucleotides, Antisense metabolism, Organ Culture Techniques, Peptides immunology, Phosphoric Monoester Hydrolases genetics, Receptors, Antigen, T-Cell agonists, Receptors, Antigen, T-Cell antagonists & inhibitors, Receptors, Antigen, T-Cell metabolism, Signal Transduction, T-Lymphocytes cytology, T-Lymphocytes metabolism, Thymus Gland cytology, Thymus Gland immunology, Thymus Gland metabolism, MicroRNAs physiology, T-Lymphocytes immunology
- Abstract
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.
- Published
- 2007
- Full Text
- View/download PDF