CD100 modulates cytotoxicity of CD8+ T cells in patients with acute myocardial infarction

Abstract

Background CD100 is an immune semaphorin family member that highly expressed on T cells, which take part in the development of acute myocardial infarction (AMI). Matrix metalloproteinases (MMPs) are important mediators for membrane-bound CD100 (mCD100) shedding from T cells to generate soluble CD100 (sCD100), which has immunoregulatory effect on T cells. The aim of this study was to investigate modulatory role of CD100 on CD8+ T cell activity in AMI patients. Methods Peripheral sCD100 and MMP-2 level, as well as mCD100 level on T cells was assessed in patients with stable angina pectoris (SAP), unstable angina pectoris (UAP), and AMI. The regulatory function of MMP-2 on mCD100 shedding, sCD100 formation, and cytotoxicity of CD8+ T cells was analyzed in direct and indirect contact co-culture system. Results AMI patients had higher peripheral sCD100 and lower mCD100 expression on CD8+ T cells in comparison with SAP, UAP, and controls. CD8+ T cells in AMI patients showed elevated direct cytotoxicity, enhanced cytokine production, and increased perforin/granzyme B secretion. Recombinant sCD100 stimulation promoted cytolytic function of CD8+ T cells in controls and AMI patients. Furthermore, AMI patients also had elevated circulating MMP-2 level. Recombinant MMP-2 stimulation induced mCD100 shedding from CD8+ T cells and sCD100 generation, resulting in enhancement of CD8+ T cell cytotoxicity in AMI patients. Conclusion Up-regulation of MMP-2 might contribute to elevation of mCD100 shedding and sCD100 formation, leading to increased cytotoxicity CD8+ T cells in AMI patients.

The role of semaphorins in cardiovascular diseases: Potential therapeutic targets and novel biomarkers

“…59,60 Patients with acute MI exhibited elevated circulating MMP-2 level, upregulation of peripheral active sSema4D expression and downregulation of mSema4D expression on CD8 + T cells, leading to an increase in CD8 + T-cell cytotoxicity. 61 These results suggest that MMP-2-induced Sema4D cleavage has a pivotal immunomodulatory role in peripheral CD8 + T cells, which might serve as a potential therapeutic target for acute MI.…”

“…Matrix metalloproteinase (MMP)‐2 is an independent and powerful predictor of all‐cause mortality in patients with ACS 58 and is also an important mediator of sSema4D formation and membrane‐bound Sema4D (mSema4D) shedding from CD8 + T cells 59,60 . Patients with acute MI exhibited elevated circulating MMP‐2 level, upregulation of peripheral active sSema4D expression and downregulation of mSema4D expression on CD8 + T cells, leading to an increase in CD8 + T‐cell cytotoxicity 61 . These results suggest that MMP‐2‐induced Sema4D cleavage has a pivotal immunomodulatory role in peripheral CD8 + T cells, which might serve as a potential therapeutic target for acute MI.…”

Post-myocardial infarction fibrosis: Pathophysiology, examination, and intervention

“…For example, B cells infiltrate into damaged myocardium within 1-7 days (Adamo et al, 2020), and B cells deficiency downregulates cytokines (e.g., TNF-α, IL-1β, IL-6, and TGF-1β) and collagen synthesis to alleviate fibrosis after MI (Mo et al, 2021). Additionally, MMP-2 increases the cytotoxicity of CD8 + T cells in acute MI patients (Li et al, 2021g). Cross-priming dendritic cells activate cytotoxic CD8 + T cells to exacerbate Frontiers in Pharmacology frontiersin.org inflammatory damage and fibrosis (Forte et al, 2021b).…”