Transcriptional regulation of inflammatory and autoimmune responses

Division Of Basic Sciences - Nci

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Abstract

In FY2025, we made significant progress toward understanding how transcriptional regulation shapes the pathogenic potential of TH17 cells during neuroinflammation. We demonstrated that the transcription factor EGR2 is selectively required for the pathogenic program of TH17 cells infiltrating the central nervous system, but not for protective TH17 cells residing in barrier tissues. Using inducible genetic models, transcriptomic analyses, and functional in vivo assays, we showed that EGR2 regulates genes critical for CNS tissue infiltration, proinflammatory cytokine production, and effector function in pathogenic TH17 cells. We further found that the requirement for EGR2 is context-dependent and shaped by tissue-specific cues and the strength of TCR signaling. These findings support our hypothesis that transcriptional control of TH17 cells is dynamically regulated by environmental and antigenic context. In contrast, protective TH17 cells in mucosal tissues remained largely unaffected by EGR2 deletion, underscoring the selective nature of this regulatory pathway. Key accomplishments include: 1. Identification of EGR2 as a critical regulator of pathogenic, but not protective, TH17 cells 2. Mapping of gene expression changes associated with EGR2-dependent TH17 cell programs in the CNS 3. Functional evidence that EGR2 deficiency in TH17 cells reduces disease severity in an animal model of CNS autoimmunity Building on this, we discovered a previously unrecognized role for GATA3-a transcription factor canonically linked to TH2 cell fate-in promoting and sustaining the pathogenicity of T-bet-expressing TH17 cells in EAE. We found that TH17 cells transiently express GATA3 during their differentiation both in vitro and in vivo. Early deletion of Gata3 using multiple conditional models impaired the generation of T-bet+ TH17 cells and reduced EAE severity. Notably, late deletion of Gata3 in an adoptive transfer model abolished disease despite intact T-bet expression, correlating with a marked reduction in GM-CSF production. RNA-Seq analysis of CNS-infiltrating CD4+ T cells from mixed bone marrow chimeras revealed that GATA3 regulates a pathogenic gene module including Egr2, Bhlhe40, and Csf2. Together, these results highlight a new transcriptional axis in which GATA3 acts upstream of EGR2 and GM-CSF to license the encephalitogenic program of TH17 cells. This work advances our understanding of the context-specific transcriptional networks that define pathogenic TH17 responses and may inform new therapeutic strategies aimed at selectively targeting neuroinflammatory T cells while preserving protective immunity.