Serpine1 negatively regulates Th1 cell responses in experimental autoimmune encephalomyelitis.

Abstract

Th1 cells are critical in experimental autoimmune encephalomyelitis (EAE). Serpine1 has been posited as an inhibitor of IFN{gamma} from T cells though its role in autoimmunity remains unclear. Here, we show that Serpine1 knockout (KO) mice develop EAE of enhanced severity relative to wild-type (WT) controls. Serpine1 overexpression represses Th1 cell cytokine production and pathogenicity, while Serpine1-KO:2D2 Th1 cells transfer EAE of increased severity in comparison to WT 2D2 Th1 cells. Notably, polarized Serpine1-KO Th1 cells display delayed expression of the Th1-specific inhibitory receptor, Tim-3. Serpine1-KO:Tim-3-Tg Th1 cells, which transgenically over-express Tim-3, showed increased expression of IFN{gamma} and reduced expression of the checkpoint molecules Lag-3 and PD-1 relative to WT Tim-3-Tg counterparts. Further, Serpine1 deficiency restored the EAE phenotype of Tim-3-Tg mice that normally develop mild disease. Together, we identify Serpine1 as a negative regulator of Th1 cells. Key pointsO_LISerpine1 inhibits EAE in a T cell-dependent manner. C_LIO_LISerpine1 is upregulated in Th1 cells and inhibits their pathogenicity. C_LIO_LISerpine1 promotes expression and function of Th1-specific inhibitory receptor Tim-3. C_LI