miRNA signature of mouse helper T cell hyper-proliferation.

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.