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miR-451 limits CD4+ T cell proliferative responses to infection in mice
Lesley M Chapman1,2, Sara K Ture1, David J Field1
1Aab Cardiovascular Research Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY, 14642, USA.
Abstract:
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.
Insights
Mice lacking microRNA-451 (miR-451) cleared malaria faster due to enhanced CD4+ T cell proliferation. This immune response is partly regulated by the Myc pathway, highlighting miR-451
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are key regulators of cellular responses, including immune reactions to pathogens like Plasmodium.
- Specific miRNAs influence host defense mechanisms during malaria infection.
Purpose of the Study:
- To investigate the role of microRNA-451 (miR-451) in regulating immune responses during blood-stage malaria.
- To elucidate the cellular and molecular mechanisms underlying miR-451's function in malaria infection.
Main Methods:
- Utilized a nonlethal mouse model of Plasmodium yoelii XNL infection.
- Compared infection clearance rates, leukocyte responses, and CD4+ T cell proliferation between wild-type (WT) and miR-451 knockout (miR-451-/-) mice.
- Analyzed Myc expression and employed RNA-Sequencing (RNA-Seq) to identify differentially expressed genes in CD4+ T cells.
Main Results:
- miR-451-/- mice exhibited faster clearance of Plasmodium infection compared to WT mice.
- A heightened leukocyte response was observed in miR-451-/- mice, primarily driven by CD4+ T cells.
- CD4+ T cells from miR-451-/- mice showed significantly increased proliferation in vitro and in vivo, linked to elevated Myc expression.
- RNA-Seq revealed over 5000 differentially expressed genes in miR-451-/- CD4+ T cells post-infection, many regulated by Myc.
Conclusions:
- miR-451 plays a regulatory role in T cell proliferation during malaria infection.
- The protective effect in miR-451 deficient mice is mediated, in part, through a Myc-dependent mechanism.
- This study identifies a novel pathway involving miR-451 and Myc in controlling T cell-mediated immunity against malaria.