An Emerging Player in the Adaptive Immune Response: MicroRNA-146a is a modulator of IL-2 expression and AICD in T lymphocytes

Background: MicroRNAs are small noncoding RNAs that actas key post-transcriptional regulators of gene expression. Acti-vation of the T cell-mediated immune response has been asso-ciated with changes in the expression of specific microRNAs.This study focuses on the functional role of microRNA-146a inT lymphocyte-mediated immune response, providing interest-ing clues on the transcriptional regulation of miR-146a duringT cell activation.Methods: Human primary CD4+/CD8+T lymphocytes werepurified from healthy donor’s PBMC. MiRNA-146a expressionwas measured by qRT-PCR. MiRNA-146a over-expression wasobtained by transducing Jurkat cells with a lentiviral vector.Results: We show that miR-146a is up-regulated during T celldifferentiation and is abundantly expressed in memory CD4+/CD8+T cells, consistently miRNA-146a is induced in primary Tlymphocytes upon TCR stimulation. Moreover, we identifiedNF-kB and c-ETS as required for the induction of miR-146a tran-scription upon TCR engagement. MiR-146a enforced expressionimpairs both AP-1 activity and IL-2 production induced by TCRstimulation. Our results also showed that miR-146a modulatesAICD: after treatment with Fas agonist CH11 apoptosis wasreduced in miR146a over-expressing lymphocytes: (24% annex-in-V+cells) comparing to control cells (44% annexin-V+cells).Finally, we identified FADD as a target of miR-146a and demon-strated that in TCR-stimulated primary T lymphocytes FADDexpression inversely correlates with miR-146a levels.Conclusion: We showed that several signalling pathways areinfluenced by miR-146a. The up-regulation of miR-146a in mem-ory T lymphocytes and the reduced apoptosis observed in miR-146a over-expressing cells are consistent with a possible role ofthis miRNA in the accumulation and/or maintenance of mem-ory T cells ‘pool’. Memory T lymphocytes are long lasting cells,less susceptible to apoptosis, thus miR-146a could be one of theanti-apoptotic factors up-regulated in memory cells.