Journal
CELL
Volume 129, Issue 1, Pages 147-161Publisher
CELL PRESS
DOI: 10.1016/j.cell.2007.03.008
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Funding
- NHLBI NIH HHS [R01-HL081612, R01 HL081612-03, R01 HL081612, R01 HL081612-01, R01 HL081612-02] Funding Source: Medline
- NIAID NIH HHS [R01 AI073724, T32 AI007328] Funding Source: Medline
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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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