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.

No abstract

MicroRNAs (miRNAs), an abundant class of ~22-nt endogenous regulatory RNAs that control gene expression at the posttranscriptional levels, have been implicated to play roles in the normal hematopoiesis and pathogenesis of leukemias. To identify “leukemic miRNAs”--miRNAs that may be oncogenes or tumor suppressors in human leukemias, we systematically cloned miRNAs from the blast cells of childhood acute lymphoblastic leukemia (ALL) patients with either a poor prognostic mixed-lineage leukemia rearrangement phenotype (MLL) or a prognostically more favorable precursor B-cell ALL phenotype (B-ALL). We have identified 87 known and 43 new human mature miRNAs, which potentially encoded by 101 known and 94 new human miRNA genes, respectively. Many newly identified miRNAs are not conserved in mouse, suggesting that systematic miRNA cloning analysis can facilitate the discovery of many novel human leukemia specific miRNAs. Interestingly, quantification of miRNA expression by real-time PCR analyses revealed that miRNAs are generally expressed at higher levels in MLL and B-ALL leukemia cells when compared to that in normal CD34+ bone marrow cells. We selected 21 highly differentially expression miRNA candidates and determined their expression in a larger group of 14 MLL patients and 16 B-ALL patients. We found that 9 miRNAs, including 4 newly identified miRNAs, were significantly differentially expressed (p < 0.05) between MLL and B-ALL subtypes. These findings demonstrate that the expression of both known and newly identified miRNA genes differs in genetically and prognostically different subgroups of ALL and normal CD34+ progenitor cells, suggesting that systematic miRNA cloning analyses and subsequent expression profiling analysis may facilitate the identification of specific signatures for leukemia classification and tumor suppressors or oncogenes that contribute to the pathogenesis of MLL and B-ALL.