miR-451 limits CD4+ T cell proliferative responses to infection in mice

Abstract

MicroRNA (miRNA) are major regulators of cell responses, particularly in stressed cell states and host immune responses. Some miRNA have a role in pathogen defense, including regulation of immune responses to Plasmodium parasite infection. Using a non-lethal mouse model of blood stage malaria infection we have found that miR-451−/− mice infected with Plasmodium yoelii XNL cleared infection at a faster rate than did wild type (WT) mice. MiR-451−/− mice had an increased leukocyte response to infection, with the protective phenotype primarily driven by CD4+ T-cells. WT and miR-451−/− CD4+ T-cells had similar activation responses, but miR-451−/− CD4+ cells had significantly increased proliferation, both in vitro and in vivo. Myc is a miR-451 target with a central role in cell cycle progression and cell proliferation. CD4+ T-cells from miR-451−/− mice had increased post-activation Myc expression. RNA-Seq analysis of CD4+ cells demonstrated over 5000 differentially expressed genes in miR-451−/− mice post-infection, many of which are directly or indirectly Myc regulated. This study demonstrates that miR-451 regulates T-cell proliferative responses in part via a Myc dependent mechanism.

Inhibition of microRNA-451 is associated with increased expression of Macrophage Migration Inhibitory Factor and mitigation of the cardio-pulmonary phenotype in a murine model of Bronchopulmonary Dysplasia

“…MicroRNA-451 (miR-451) is a 22 base pair (bp) sequence of complementary nucleotides that has been shown to bind to the 3'untranslated (UTR) region of MIF mRNA leading to inhibition of protein synthesis [14,15]. miR-451 has also been shown to reduce angiogenesis in colorectal cancer cells by targeting the interleukin -6 receptor (IL-6R) [16] and to decrease T-cell responses to infection by inhibiting the expression of the regulatory gene, myc [17]. By inhibiting the expression of the regulatory protein Tyrosine 3-Monooxygenase/ Tryptophan 5-Monooxygenase Activation Protein Zeta (YWHAZ), miR-451 has been found to promote proapoptotic pathways involving the transcription factor forkhead box O3 (FOXO3) [18,19] and to reduce expression of pro-inflammatory cytokines in dendritic cells exposed to influenza virus [20].…”

gga-miR-451 Negatively Regulates Mycoplasma gallisepticum (HS Strain)-Induced Inflammatory Cytokine Production via Targeting YWHAZ

“…miR-451 had been found to be ubiquitously expressed in different tissues [ 39 , 40 ]. Previous studies have suggested that miR-451 function in multiple cellular processes such as migration, invasion, cycle, proliferation, apoptosis, and it is an important and potential target in human cancer treatment [ 30 , 41 , 42 , 43 ]. However, little is known about the function and mechanism of miR-451 involving in MG-induced inflammation development and progression.…”

Control of Immunoregulatory Molecules by miRNAs in T Cell Activation

“…Another molecule involved in cell cycle progression is CDK4, a target of miR-491 in mouse CD8 + T cells ( 47 ). MYC is a transcription factor involved in cell cycle and proliferation, is targeted by let-7 in mouse CD8 + T cells ( 48 ) and by miR-451 in both mouse ( 49 ) and human ( 50 ) CD4 + T cells.…”