Study On The Function Of RNA Editing Enzyme ADAR1 In T Cell Development

The mechanisms accounting for self-tolerance by the immune system and clonal selection of functional lymphocytes that only react to alien antigens are of central concern to immunology. Lymphoid progenitors arising from bone marrow stem cells migrate into thymus where they interact with the cortical and medullar thymic epithelial cells to differentiate into mature T cells. From the progenitor to mature T cell stage, thymocytes have been phenotypically characterized to distinct stages featuring the differentiation antigen expression of CD4 and CD8, defined as double negative (DN), double positive (DP) and single positive (SP) cells. Based on the transient expression of CD44 and CD25, DN cells are further categorized into DN1, 2, 3 and 4 subpopulations. T cell development is an ordered process through multiple differentiation steps, and T cell receptor (TCR) expression is one of the most critical events in the differentiation and maturation processes. TCRβrecombination begins at the DN2 stage and continues to DN3 stage. Functional TCRβis expressed on the surface of DN3 cells, where it associates with pre-TCRαand CD3 elements to form the Pre-TCR which provides signals for proliferation, survival and further maturation. At DP stage, TCRαundergoes V(D)J recombination and both TCRαand TCRβare expressed to form the cell surface TCRα/βreceptors. Functional T cell clones subsequently undergo the positive and negative selection and lineage commitment of CD4 or CD8 SP cells. The mechanism responsible for cell fate during the selection is yet to be fully understood.Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme and plays an essential role in embryonic hematopoiesis. Through its deamination activity, ADAR1 converts adenosine to inosine in RNA molecules (A to I RNA editing); inosine is equivalent to guarnosine in Watson-Crick structure and during protein translation. A-I RNA editing therefore durably modifies sequences of targeted RNAs and can alter proteins that they encode. Proteins coded by edited RNAs, such as GluR-B and 5-HT2cR exhibit dramatically different properties from the genome coded forms. Splicing sites can be generated or eliminated by this A to I conversion. Some microRNA precursors were edited, which consequently modulated the efficacy of mature microRNA genesis or shifts their targets. In addition, ADAR1 has been proposed to participate, through protein-protein interaction, in the processes of RNA transportation, degradation, and regulation of gene expression. Our data has demonstrated an essential role of ADAR1 in T cell development which was associated with TCRβchain expression.ADAR1 plays an important role in host antiviral mechanisms and immunity. Interferons induce the upregulation of ADAR1, thus raising the possibility that ADAR1 functions in host defense mechanisms against viral infection and inflammation. For instance, ADAR1 edits the hepatitis C virus RNA genome and inhibits its replication. Inosine-containing mRNAs increase in T lymphocytes and macrophages stimulated with a variety of inflammatory mediators, including tumor necrosis factor-αand interferon-γ. Furthermore, ADAR1 interacts with nuclear factor 90 (NF90) family proteins. Dysfunction of the A-I RNA editing mechanism can cause human diseases or pathophysiology, Many human diseases related to A-I RNA editing has recently become known.The RNA editing enzyme ADAR1 has been shown to be essential for embryonic development and for the survival of differentiating hematopoietic progenitors. We recently reported that RNA editing activity of ADAR1 was required for the differentiation of adult hematopoietic progenitor cells. ADAR1 is expressed throughout T cell development in the thymus. However, little is understood about its function because of the embryonic lethality of traditional ADAR1-null mutations. In order to explore the function of ADAR1 in T cells, we generated a mouse model in which ADAR1 was specifically deleted in the early stage of T cell differentiation. we found that ADAR1 is required for T cell development at the DN stage. Loss of ADAR1 caused cell death in the progenitors at the DN4 stage and prevented T cell maturation in the thymus. TCRβexpressing cells preferentially diminished in the absence of ADAR1 although the recombination of TCRβloci was shown to be ADAR1-independent. Interruption of IFN signaling was associated with the defect of ADAR1 deficiency. These findings demonstrated an essential role for the RNA editing enzyme ADAR1 supporting in T cell survival after pre-TCR expression and raise the prospect that RNA editing contributes to immunologic homeostasis and is a heretofore unrecognized regulator of T-cell fate during clonal selection.