T-Cell–Mediated Lysis of Endothelial Cells in Acute Coronary Syndromes

Abstract

Background-CD4 T lymphocytes accumulate in unstable plaque. The direct and indirect involvement of these T cells in tissue injury and plaque instability is not understood. Methods and Results-Gene profiling identified perforin, CD161, and members of the killer-cell immunoglobulin-like receptors as being differentially expressed in CD4 ϩ CD28 null T cells, a T-cell subset that preferentially infiltrates unstable plaque. Frequencies of CD161 ϩ and perforin-expressing CD4 T cells in peripheral blood were significantly increased in patients with unstable angina (UA). CD161 appeared on CD4 ϩ CD28 null T cells after stimulation, suggesting spontaneous activation of circulating CD4 T cells in UA. Perforin-expressing CD4 ϩ T-cell clones from patients with UA exhibited cytotoxic activity against human umbilical vein endothelial cells (HUVECs) in redirected cytotoxicity assays after T-cell receptor triggering and also after stimulation of major histocompatibility complex class I-recognizing killer-cell immunoglobulin-like receptors. HUVEC cytolysis was dependent on granule exocytosis, as demonstrated by the paralyzing effect of pretreating CD4 ϩ CD28 null T cells with strontium. Incubation of HUVECs with C-reactive protein (CRP) increased HUVEC lysis in a dose-dependent fashion. Conclusions-In patients with UA, CD4 T cells undergo a change in functional profile and acquire cytotoxic capability.Cytotoxic CD4 T cells effectively kill endothelial cells; CRP sensitizes endothelial cells to the cytotoxic process. We propose that T-cell-mediated endothelial cell injury is a novel pathway of tissue damage that contributes to plaque destabilization. The sensitizing effect of CRP suggests synergy between dysregulated T-cell function and acute phase proteins in acute coronary syndromes. (Circulation. 2002;105:570-575.)

Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

“…Such T cells have altered tissue trafficking (45), are biased toward proinflammatory action, and preferentially interact with mesenchymal cells, such as synovial fibroblasts, in peripheral tissues (46). Senescent CD4 T cells accumulate in unstable atherosclerotic plaques and have been implicated in plaque destabilization, providing a link to the increased cardiovascular risk in RA patients (47)(48)(49). Premature senescence of the RA immune system is not limited to the memory T cell pool; it also involves naive T cells (43), the reserve pool of T cells that protect from infection and malignancy and enable tissue repair.…”

Granzyme B in Atherosclerosis and Transplant Vascular Disease: Association with Cell Death and Atherosclerotic Disease Severity

“…Instead, Nakajima et al (33) have recently shown that a subset of CD4ϩ T cells that are abundant in patients with atherosclerosis express perforin and that these are potent mediators of granule-mediated apoptosis of endothelial cells. The expression of perforin by this subset of T cells is strongly correlated with unstable angina, suggesting a key role for the granzyme/perforin pathway in acute coronary syndromes.…”

Increased Soluble CD137 Levels and CD4+ T‐Cell‐Associated Expression of CD137 in Acute Atherothrombotic Stroke

“…Moreover, CD28– T cells were shown to produce the cytotoxic molecules perforin and granzyme B, which resulted in cytolysis of the endothelium in vitro 29, 30. CD4+CD28– T cells have been found in patients with cerebrovascular and cardiovascular diseases such as acute coronary syndrome27, 31 and stroke 32, 33, 34.…”

“…In the CD137‐deficient atherosclerotic vessels of ApoE − / − CD137 − / − mice, crosslinking CD137L activation with soluble CD137 protein ex vivo activated CD137L signaling and led to the release of proinflammatory cytokines, such as TNF‐α and monocyte chemotactic protein‐1 (MCP‐1) 11. In ACS patients, blocking the CD137 pathway in vitro remarkably reduced the production of TNF‐α and IFN‐γ from circulating CD4+CD28– T cells, which were reported to induce rupture of atherosclerotic plaques by direct cytolysis of arterial smooth muscle and endothelial cells 27, 30. In our serial study, despite an irregular change of lymphocyte counts in the stroke patients, CD137 expression in the CD4+ and CD4+CD28– T cells displayed a decreasing trend at 3 and 14 days posttreatment with statin, a well‐known cholesterol‐lowering drug with multiple antiinflammatory properties 36.…”