IL-1-induced Bhlhe40 identifies pathogenic TH cells in a model of autoimmune neuroinflammation

Abstract

Abstract The features that define autoreactive TH cell pathogenicity remain obscure. We have previously shown that TH cells require the transcription factor Bhlhe40 to mediate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Here, using Bhlhe40-EGFP reporter mice and analyzing both polyclonal and TCR transgenic CD4+ T cells, we found that Bhlhe40 expression was heterogeneous after EAE induction. Bhlhe40-expressing CD4+ T cells displayed marked production of IFN-γ, IL-17A, and GM-CSF, while exhibiting reduced expression of the anti-inflammatory cytokine IL-10 and the regulatory T cell transcription factor Foxp3. In adoptive transfer EAE models Bhlhe40-deficient TH1 and TH17 cells were both nonencephalitogenic. Pertussis toxin (PTX), a classical coadjuvant for actively induced EAE, promoted IL-1β production by myeloid cells in the draining lymph node and served as a strong stimulus for Bhlhe40 expression in TH cells. Furthermore, PTX coadjuvanticity was Bhlhe40 dependent. IL-1β induced Bhlhe40 expression in polarized TH17 cells, and Bhlhe40-expressing cells exhibited an encephalitogenic transcriptional signature. In vivo, IL-1R signaling was required for full Bhlhe40 expression by TH cells after immunization. Overall, we demonstrate that Bhlhe40 expression identifies encephalitogenic TH cells and define a PTX-IL-1-Bhlhe40 pathway active in EAE.