Cutting Edge: Serpine1 Negatively Regulates Th1 Cell Responses in Experimental Autoimmune Encephalomyelitis

Author:

Akbar Irshad1ORCID,Tang Ruihan2,Baillargeon Joanie1,Roy Andrée-Pascale1,Doss Prenitha Mercy Ignatius Arokia1,Zhu Chen2ORCID,Kuchroo Vijay K.234,Rangachari Manu15

Affiliation:

1. *Axe Neurosciences, Centre de Recherche du CHU de Québec–Université Laval, Québec, Québec, Canada

2. †Evergrande Center for Immunologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA

3. ‡Ann Romney Center for Neurologic Diseases, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA

4. §Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA

5. ¶Department of Molecular Medicine, Laval University, Québec, Québec, Canada

Abstract

Abstract Th1 cells are critical in experimental autoimmune encephalomyelitis (EAE). Serine protease inhibitor clade E1 (Serpine1) has been posited as an inhibitor of IFN-γ from T cells, although its role in autoimmunity remains unclear. In this study, 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, whereas Serpine1-KO:2D2 Th1 cells transfer EAE of increased severity in comparison with WT 2D2 Th1 cells. Notably, polarized Serpine1-KO Th1 cells display delayed expression of the Th1-specific inhibitory receptor, Tim-3 (T cell Ig and mucin–domain containing-3). Serpine1-KO:Tim-3-Tg Th1 cells, which transgenically overexpress Tim-3, showed increased expression of IFN-γ and reduced expression of the checkpoint molecules Lag-3 and PD-1 relative to WT Tim-3-Tg counterparts. Furthermore, Serpine1 deficiency restored the EAE phenotype of Tim-3-Tg mice that normally develop mild disease. Taken together, we identify Serpine1 as a negative regulator of Th1 cells.

Funder

Gouvernement du Canada | Canadian Institutes of Health Research

FRQ | Fonds de Recherche du Québec - Santé

Multiple Sclerosis Society of Canada

Publisher

The American Association of Immunologists

Subject

Immunology,Immunology and Allergy

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