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

MicroRNAs (miRNAs) are major regulators of cell responses, particularly in stressed cell states and host immune responses. Some miRNAs have a role in pathogen defense, including regulation of immune responses to Plasmodium parasite infection. Using a nonlethal 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 postactivation Myc expression. RNA-Seq analysis of CD4⁺ cells demonstrated over 5000 differentially expressed genes in miR-451^−/− mice postinfection, 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.