miR-146a and miR-155 Expression Levels in Acute Graft-Versus-Host Disease Incidence

We show that microRNA-155 (miR-155) is upregulated in primary effector and effector memory CD8+ T cells but is low in naive and central memory cells. Anti-viral CD8+ T cell responses and viral clearance were impaired in miR-155 deficient (miR-155-KO) mice, and this defect was intrinsic to CD8+ T cells as miR-155-KO CD8+ T cells mounted greatly reduced primary and memory responses. Conversely, miR-155 overexpression augmented anti-viral CD8+ T cell responses in vivo. Gene expression profiling of miR-155-KO CD8+ T cells revealed increased type I interferon signaling and sensitivity. Inhibiting STAT1 or IRF7 increased miR-155-KO CD8+ T cell responses in vivo. We report a novel role for miR-155 in regulating IFN responsiveness and CD8+ T cell responses against pathogens in vivo.

MicroRNAs (miRNAs) are found in most metazoan organisms as well as in viruses and are implicated in an increasingly wide variety of biological processes in animals. Here, Taganov et al. discuss the role of miRNAs in the innate immune response to microbial infection.

Many microRNAs (miRNAs) are co-regulated during the same physiological process but the underlying cellular logic is often little understood. The conserved, immunomodulatory miRNAs miR-146 and miR-155, for instance, are co-induced in many cell types in response to microbial lipopolysaccharide (LPS) to feedback-repress LPS signalling through Toll-like receptor TLR4. Here, we report that these seemingly co-induced regulatory RNAs dramatically differ in their induction behaviour under various stimuli strengths and act non-redundantly through functional specialization; although miR-146 expression saturates at sub-inflammatory doses of LPS that do not trigger the messengers of inflammation markers, miR-155 remains tightly associated with the pro-inflammatory transcriptional programmes. Consequently, we found that both miRNAs control distinct mRNA target profiles; although miR-146 targets the messengers of LPS signal transduction components and thus downregulates cellular LPS sensitivity, miR-155 targets the mRNAs of genes pervasively involved in pro-inflammatory transcriptional programmes. Thus, miR-155 acts as a broad limiter of pro-inflammatory gene expression once the miR-146 dependent barrier to LPS triggered inflammation has been breached. Importantly, we also report alternative miR-155 activation by the sensing of bacterial peptidoglycan through cytoplasmic NOD-like receptor, NOD2. We predict that dose-dependent responses to environmental stimuli may involve functional specialization of seemingly co-induced miRNAs in other cellular circuitries as well.