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

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 À/À 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.

Hemostasis and tumor immunity

“… 34 More recent studies have shown that PAR‐1 signaling accelerates TCR‐induced calcium mobilization and facilitates polarized secretion of cytotoxic granules at the immunological synapse in human T cells. 35 Consistent with a role for the thrombin/PAR‐1 axis in T‐cell effector functions, these authors showed that CD8+ T cells deficient in PAR‐1 have impaired clearance of lymphocytic choriomeningitis virus in vivo. Together, these studies implicate CD8+ T cell‐associated PAR‐1 as a relevant thrombin target, and strongly suggest that thrombin promotes crucial T‐cell effector function.…”

Transcriptional profiles of functionally distinct HLADR+CD38+ CD8 T cells subsets from acute febrile dengue patients

“…Of these, PAR1 is a high affinity receptor for activated Thrombin and studies in murine models have shown that PAR1 expression accelerates calcium mobilization, and is involved in cytotoxic T cell function. Further, T cells from PAR -/- mice have dampened cytokine producing ability suggesting that PAR1/F2R might have a role in T cell function (83). However, our data does not provide any clues towards functionality that that could be uniquely attributed to the CD69 + IFNγ - subset suggesting that there might be some degree of redundancy in the function of PAR1.…”

A flow-cytometry-based assay to assess granule exocytosis and GZB delivery by human CD8 T cells and NK cells

“… 2 , 3 Using this assay, we evaluated the role of the Protease Activated Receptor-1 in the cytotoxic function of human CD8 T cells, and PAR1 deficient murine virus-specific CD8 T cells. 1 …”

“… 11 In addition, using a FAS deficient target cells, substrates that detect both GZB and caspase 8 activation can also be used for evaluation of the granule exocytosis pathway. 1 , 11 , 12 , 13 …”

“…Using this flow cytometry protocol two important cellular events can be detected, the delivery and activity of GZB inside the live target cells before undergoing cell death by apoptosis, and the degranulation of CD8 T cells. 1 We also present an additional application of this assay for evaluation of the ex-vivo cytotoxicity of human NK cells from PBMCs using a human immortalized myelogenous leukemia cell line K562 as target cells.…”