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Eri1 Regulation of Lymphocyte MicroRNA Homeostasis and Effector Functions


MicroRNAs (miRNAs) are emerging as important components of the epigenetic landscape that shape immune cell differentiation and effector functions. MiRNA-deficient T helper (Th) and natural killer (NK) lymphocytes show severe defects in differentiation, survival, proliferation, and effector functions, suggesting that miRNAs can modulate all of these processes. The study of individual miRNAs as well as global miRNA regulation are important steps in understanding the contribution miRNAs make to establishing lineage-specific gene expression programs.

The first part of this dissertation describes a method for profiling small RNAs in lymphocytes by high-throughput sequencing. We then apply this technique to defining the miRNA repertoire in Th cells actively differentiating into Th1 or Th2 subsets. Consistent with profiling experiments from fully polarized Th1 and Th2 cells, differentiating Th1 and Th2 cells had highly similar miRNA expression profiles as determined by both miRNA microarray and deep sequencing. There was, however, a subtle enrichment of miR-146a, miR-155, and miR-31 in differentiating Th1 cell cultures, and members of the 23b~27b~24-1 cluster were more highly expressed in Th2 cell cultures. These profiling studies served as the basis for a screen of abundantly expressed Th cell miRNAs that influence cytokine production in miRNA-deficient T cells.

We next sought to determine if the conserved 3'-to-5' exoribonuclease Eri1 regulates miRNA abundance and effector functions in lymphocytes. Eri1-deficient mice surprisingly showed cell-intrinsic defects in the development, receptor acquisition, and maturation of NK cells, which play a critical role in early host defense to infected and transformed cells. Furthermore, Eri1 was required for immune-mediated control of mouse cytomegalovirus (MCMV) infection. Antigen-specific Ly49H+ NK cells deficient in Eri1 failed to expand efficiently during MCMV infection, and virus-specific responses were also diminished among Eri1-deficient T cells. We identified miRNAs as the major endogenous small RNA target of Eri1 in mouse lymphocytes. Both NK and T cells deficient in Eri1 displayed a global, sequence-independent increase in miRNA abundance. Taken together, these studies demonstrate an important role for Eri1 in posttranscriptional RNA regulation and in lymphocyte development and antiviral immunity.

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