CD84 Links T Cell and Platelet Activity in Cerebral Thrombo-Inflammation in Acute Stroke

Abstract

Rationale: Ischemic stroke is a leading cause of morbidity and mortality worldwide. Recanalization of the occluded vessel is essential but not sufficient to guarantee brain salvage. Experimental and clinical data suggest that infarcts often develop further due to a thromboinflammatory process critically involving platelets and T cells, but the underlying mechanisms are unknown. Objective: We aimed to determine the role of CD (cluster of differentiation)-84 in acute ischemic stroke after recanalization and to dissect the underlying molecular thromboinflammatory mechanisms. Methods and Results: Here, we show that mice lacking CD84—a homophilic immunoreceptor of the SLAM (signaling lymphocyte activation molecule) family—on either platelets or T cells displayed reduced cerebral CD4 + T-cell infiltration and thrombotic activity following experimental stroke resulting in reduced neurological damage. In vitro, platelet-derived soluble CD84 enhanced motility of wild-type but not of Cd84 −/− CD4 + T cells suggesting homophilic CD84 interactions to drive this process. Clinically, human arterial blood directly sampled from the ischemic cerebral circulation indicated local shedding of platelet CD84. Moreover, high platelet CD84 expression levels were associated with poor outcome in patients with stroke. Conclusions: These results establish CD84 as a critical pathogenic effector and thus a potential pharmacological target in ischemic stroke.

T Cell Response in Ischemic Stroke: From Mechanisms to Translational Insights

“…Blocking either GPIb or its ligand VWF A1 domain with an antibody, or their genetic deletion, significantly reduced the number of infiltrated T cells and infarct volume (92)(93)(94). Another platelet-born pro-infiltration factor is CD84, a soluble homophilic immunoreceptor that is shed from platelets after ischemic stroke (70). It binds to CD84 on T cells and enhances CD4+ lymphocyte migration in vitro (70).…”

“…Another platelet-born pro-infiltration factor is CD84, a soluble homophilic immunoreceptor that is shed from platelets after ischemic stroke (70). It binds to CD84 on T cells and enhances CD4+ lymphocyte migration in vitro (70). Mice deficient in platelet or T cell CD84 developed smaller infarct volumes and had fewer infiltrated T cells (70).…”

The association of neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, and lymphocyte to monocyte ratio with post-thrombolysis early neurological outcomes in patients with acute ischemic stroke

“…Numerous studies have demonstrated that neuroinflammatory response plays an essential role in the pathophysiology of ischemic stroke [ 11 – 14 ]. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR) have recently been reported as potential novel biomarkers of baseline inflammatory process and could serve as outstanding predictors in patients with ischemic stroke [ 15 , 16 ].…”

Neuroprotective Strategies in Aneurysmal Subarachnoid Hemorrhage (aSAH)

“…Again, the beneficial effect was not associated with an increased risk of bleeding. Recent studies in mouse models of stroke have provided further evidence for T-cell interactions with platelets [ 144 ].…”