miR-181a Is an Intrinsic Modulator of T Cell Sensitivity and Selection

• Published in: Cell Vol. 129; no. 1; pp. 147 - 161
• Main Authors: Li, Qi-Jing, Chau, Jacqueline, Ebert, Peter J.R., Sylvester, Giselle, Min, Hyeyoung, Liu, Gwen, Braich, Ravi, Manoharan, Muthiah, Soutschek, Juergen, Skare, Petra, Klein, Lawrence O., Davis, Mark M., Chen, Chang-Zheng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06-04-2007
• 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; MicroRNAs - physiology; 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 - immunology; T-Lymphocytes - metabolism; Thymus Gland - cytology; Thymus Gland - immunology; Thymus Gland - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2007.03.008

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.