The Role of the Transcription Factor Ets-1 in B Cell Tolerance
Russell, Lisa Marie
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The transcription factor Ets-1 is highly expressed in lymphoid organs and has been shown to be important in both B and T cell development and function. Mice in which Ets-1 has been deleted develop an autoimmune syndrome with B and T cell activation, lymphocyte infiltration into target organs, autoantibodies and immune complexes in the kidney. Activation of autoreactive B cells and their differentiation into autoantibody-secreting plasma cells is thought to be dependent either on the presence of appropriate T cell help or on co-stimulatory activity of B cell-intrinsic TLR receptors. To further define the role of these two pathways in triggering autoreactive B cell differentiation in the absence of Ets-1, Ets-1 -/- mice were crossed to mice deficient in the key TLR adaptor protein MyD88 as well as to mice deficient in αβ T cells (TCRβ -/- ). Analysis of Ets-1 -/- /MyD88 -/- mice and Ets-1 -/- /TCRβ -/- mice as well as triple knockout Ets-1 -/- /MyD88 -/- /TCRβ -/- mice showed both pathways play a role in driving autoimmune disease in the absence of Ets-1. However, autoimmune disease was not completely abolished in Ets-1 -/- /MyD88 -/- /TCRβ -/- mice, suggesting additional pathways may play a role or perhaps that no trigger is needed for differentiation of Ets-1 -/- B cells. We used mixed bone marrow chimeras to further define B cell-intrinsic versus B cell-extrinsic factors contributing to the pathogenesis of disease in Ets-1 -/- mice. Increased differentiation of Ets-1 -/- B cells into plasma cells was found to be a B cell-intrinsic phenomenon. Given the B cell-intrinsic hyper-differentiation of Ets-1 -/- B cells into plasma cells, we hypothesized that there might be defects in establishing B cell tolerance to self-antigens. Indeed, Ets-1 is required for the maintenance of peripheral B cell tolerance in transgenic mouse models of autoreactive B cells, but is dispensable for central tolerance in the bone marrow in such models. Ets-1 is required to prevent premature B cell differentiation by inhibiting Blimp-1 repression of its target genes as well as by transactivating key early B cell identity genes such as Pax5. Given that the human ETS1 gene has recently been identified as a susceptibility locus for human immunopathological syndromes, our results shed important light on how Ets-1 controls B cell functions. Future studies to further delineate the cellular contributions to disease will be made possible with the use of mice harboring an Ets-1 floxed allele, which we are currently developing.