Saturday, April 14, 2007

Micro RNA sets sensitivity of T cell

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.

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