Abstract
Helper T cells from a mutant mouse model, LAT Y136F, hyper-proliferate and cause a severe lymphoproliferative disease that kills the mice by six months of age. LAT Y136F mice carry a tyrosine to phenylalanine mutation in the Linker for Activation of T cells (LAT) gene. This mutation leads to a number of changes in T cells that result in altered cytokine production including increased IL-4 production, increased proliferation, and decreased apoptosis. Hyper-proliferation of the mutant T cells contributes to lymphadenopathy, splenomegaly, and multi-organ T cell infiltration. miRNAs are short non-coding RNAs that regulate expression of cohorts of genes. This study investigates which miRNAs are expressed in LAT Y136F T cells and compares these to miRNAs expressed in wild type T cells that are undergoing proliferation in two other settings. The first setting is homeostatic proliferation, which was modeled by adoptive transfer of wild type T cells into T cell-deficient mice. The second setting is proliferation in response to infection, which was modeled by infection of wild type mice with the nematode H. polygyrus. By comparing miRNA expression in these three proliferative states (LAT Y136F hyper-proliferation, homeostatic proliferation and proliferation in response to H. polygyrus infection) to expression in wild type naïve CD4+ T cells, we found miRNAs that were highly regulated in all three proliferative states (miR-21 and miR-146a) and some that were more specific to individual settings of proliferation such as those more specific for LAT Y136F lymphoproliferative disease (miR-669f, miR-155 and miR-466a/b). Future experiments that modulate levels of the miRNAs identified in this study may reveal the roles of these miRNAs in T cell proliferation and/or lymphoproliferative disease.
Highlights
During an immune response to an infectious agent, a few, rare T cells specific for a particular antigen are activated and proliferate
We have examined miRNA levels in T cells proliferating during a normal immune response to helminth infection, during homeostatic proliferation, and in Linker for Activation of T cells (LAT) Y136F lymphoproliferative disease in an effort to identify miRNAs that direct hyper-proliferation in LAT Y136F T cells and that are involved in helper T cell proliferation in general
We investigated miRNAs regulated in CD4+ helper T cell proliferative states as well as identified miRNAs that potentially control hyper-proliferation in mutant LAT Y136F T cells
Summary
During an immune response to an infectious agent, a few, rare T cells specific for a particular antigen are activated and proliferate. T cell proliferation is first initiated by binding of foreign antigen presented by a major histocompatibility complex molecule to the T cell antigen receptor (TCR) This binding event, along with engagement of other cell surface receptors, leads to the activation of various transcription factors through the action of signaling mediators. Hyper-proliferative LAT Y136F mutant T cells share characteristics with two different proliferative states induced in wild type CD4+ T cells In both of these states wild type T cells proliferate in response to a trigger, and T cell numbers return to normal. MiRNA mmu-miR-150 mmu-miR-15b mmu-miR-30b mmu-let-7f mmu-miR-21 mmu-let-7c mmu-miR-181a mmu-miR-15a mmu-let-7b mmu-miR-342-3p mmu-miR-26b mmu-miR-669f mmu-miR-151-3p mmu-miR-29c mmu-miR-151-5p mmu-miR-155 mmu-miR-467f mmu-miR-378 mmu-miR-466a/b-3p mmu-miR-146a mmu-miR-145 mmu-miR-10a mmu-miR-27a mmu-miR-361 mmu-miR-22 mmu-miR-423-5p mmu-miR-547 mmu-miR-338-5p mmu-let-7i mmu-miR-883b-3p mmu-miR-1949 mmu-miR-340-5p mmu-miR-544 mmu-miR-148a mmu-miR-139-5p mmu-miR-132 mmu-miR-23a mmu-miR-539 mmu-miR-93 mmu-miR-125a-5p mmu-miR-130b mmu-let-7e mmu-miR-350 mmu-miR-24 mmu-miR-107 mmu-miR-1902
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
