MicroRNAs are single-stranded RNA molecules, averaging 22 nucleotides in length and encoded in the genome, that regulate the expression of other genes. MicroRNA and the process of “RNA interference” were discovered only a few years ago. The miRNA miR-181a was known to be hightly expressed in the thymus and to function in T cell development. Li and colleagues investigated the function of this miRNA by manipulating its expression in T cells. Forced (ectopic) expression makes T cells more sensitive to stimulatory peptides, generating a stronger calcium flux with about half as many peptides (Figure, left panel). Even an antagonist peptide, which usually turns off T cells, triggers calcium flux (right panel) and growth factor (IL-2) secretion from T cells overexpressing miR-181a. This apparently occurs by miR-181a repressing transcripts encoding phosphatases, including DUSP5 and 6, SHP-2 (but not SHP-1), and PTPN22. For example, phosphorylated ERK (the substrate for DUSP6) remains high longer after activation of T cells expressing more miR-181a. Knocking down individual phosphatases did not overcome miR-181a-enhanced sensitivity, suggesting that multiple pathways are targeted. However, overexpression of DUSP6 or DUSP5 or SHP-2 (using modified sequences that are not recognized by miR-181a) restored repression in T cells expressing miR-181a. The authors designed an “antagomir” to block miR-181a and found it disrupted selection of antigen-specific T cells in the thymus. This new and unexpected mechanism of regulation may be important in understanding T cell development and activation.
Cell. 2007 Apr 6;129(1):147-61. “miR-181a Is an Intrinsic Modulator of T Cell Sensitivity and Selection.” Li QJ, Chau J, Ebert PJ, Sylvester G, Min H, Liu G, Braich R, Manoharan M, Soutschek J, Skare P, Klein LO, Davis MM, Chen CZ.
Saturday, April 14, 2007
Micro RNA sets sensitivity of T cell
at 7:51 AM
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