Ets1 Controls the Development of B Cell Autoimmune Responses in a Cell-Intrinsic Manner

Ets1 is emerging as a key transcription factor that is required to prevent autoimmunity in mice and humans. Ets1 is expressed in both B and T cells, and mice lacking Ets1 are characterized by excess B and T cell activation, leading to enhanced formation of Ab-secreting cells and high titers of autoantibodies. In humans, genome-wide association studies have detected associations of single nucleotide polymorphisms in the human ETS1 gene with autoimmune diseases, including lupus. An increased fraction of CD4(+) T cells from Ets1(−/−) mice have an activated effector-memory phenotype, and there are aberrations in differentiation that contribute to the autoimmune phenotype. In vitro studies of B cells suggest that Ets1 may have B cell–intrinsic effects as well. To confirm B cell–intrinsic roles for Ets1, we crossed CD19-Cre mice to mice with a floxed allele of Ets1. Mice with a B cell–specific deletion of Ets1 show increases in B cell activation, numbers of Ab-secreting cells, and levels of autoantibodies, despite the fact that T cells are normal. However, when compared with conventional Ets1 knockout mice, mice with B cell–specific loss of Ets1 have a significantly milder phenotype. These results demonstrate that Ets1 is required in B cells to prevent autoimmune responses but that loss of Ets1 activity in other cell types is required for maximal autoimmune phenotypes.