Qi-Jing Li, Jacqueline Chau,
Peter J R Ebert,
Giselle Sylvester,
Hyeyoung Min,
Gwen Liu,
Ravi Braich,
Muthiah Manoharan,
Juergen Soutschek,
Petra Skare,
Lawrence O Klein,
Mark M Davis,
Chang-Zheng Chen
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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.
Cell 05/2007; 129(1):147-61. · 32.40 Impact Factor
