The role of protease-activated receptor 1 signaling in CD8 T cell effector functions

Hui Chen; Mindy Smith; Jasmin Herz; Tong Li; Rebecca Hasley; Cecile Le Saout; Ziang Zhu; Jie Cheng; Andres Gronda; José A Martina; Pablo M Irusta; Tatiana Karpova; Dorian B McGavern; Marta Catalfamo

doi:10.1016/j.isci.2021.103387

The role of protease-activated receptor 1 signaling in CD8 T cell effector functions

iScience. 2021 Oct 30;24(11):103387. doi: 10.1016/j.isci.2021.103387. eCollection 2021 Nov 19.

Authors

Hui Chen^{1

2}, Mindy Smith², Jasmin Herz³, Tong Li¹, Rebecca Hasley², Cecile Le Saout², Ziang Zhu¹, Jie Cheng¹, Andres Gronda⁴, José A Martina⁵, Pablo M Irusta⁴, Tatiana Karpova⁶, Dorian B McGavern³, Marta Catalfamo¹

Affiliations

¹ Department of Microbiology and Immunology, Georgetown University School of Medicine, Washington, DC, USA.
² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
³ Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
⁴ Department of Human Science, Georgetown University, Washington, DC, USA.
⁵ Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
⁶ Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Abstract

CD8 T cells are essential for adaptive immunity against viral infections. Protease activated receptor 1 (PAR1) is expressed by CD8 T cells; however, its role in T cell effector function is not well defined. Here we show that in human CD8 T cells, PAR1 stimulation accelerates calcium mobilization. Furthermore, PAR1 is involved in cytotoxic T cell function by facilitating granule trafficking via actin polymerization and repositioning of the microtubule organizing center (MTOC) toward the immunological synapse. In vivo, PAR1^-/- mice have reduced cytokine-producing T cells in response to a lymphocytic choriomeningitis virus (LCMV) infection and fail to efficiently control the virus. Specific deletion of PAR1 in LCMV GP33-specific CD8 T cells results in reduced expansion and diminished effector function. These data demonstrate that PAR1 plays a role in T cell activation and function, and this pathway could represent a new therapeutic strategy to modulate CD8 T cell effector function.

Keywords: Immune response; Immunology; Molecular biology.

Grants and funding

R01 AI145549/AI/NIAID NIH HHS/United States