TH17 cells have been implicated in the pathogenesis of most common autoimmune and inflammatory diseases. However, not all TH17 cells are pathogenic. The goal of this project is to identify novel transcriptional regulators that regulate differentiation of TH17 cells with immunoregulatory versus pathogenic effector functions. We have focused on the role of Egr family of transcription factors in TH17 differentiation because high resolution transcriptional profiling predicted that Egr1 and Egr2 could function as positive regulators of TH17 differentiation program. Our studies have shown that the transcription factor Egr2, but not Egr1, is a positive regulator of TH17 cell differentiation. Egr2 augmented the expression of the TH17 lineage-signature genes: Rorc, Il17a, Il17f and Il22. Interestingly, over-expression of Egr2 in non-pathogenic TH17 cells induced the expression of pathogenicity-associated genes (e.g. Il22, Tbx21, Ccl3) and augmented the expression of immunoregulatory genes (e.g. Foxp3, Il9, Il10). To determine whether Egr2 was required for the development of immunoregulatory or pathogenic TH17 cells, we have generated mice with peripheral T cell-specific deletion of Egr2 (Egr2f/f hCD2-Cre+). In our future studies, we investigate the effects of T cell-specific Egr2-deficiency on the differentiation and effector function CD4+ T cells in the context of infections and autoimmunity.
