miR-181a is an intrinsic modulator of T cell sensitivity and selection |
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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 |
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Institution: | Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. |
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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. |
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