De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes

The inflammatory infiltrate in atherosclerotic plaque is composed of T cells and macrophages. CD4(+) T cells with a unique phenotype, CD4(+)CD28(null), are preferentially recruited into culprit lesions. These T cells are distinct from classic CD4(+)CD28(+) T cells in gene expression and function, including their ability to mediate cytolysis. In this study, we have investigated the regulation of CD4(+)CD28(null) T-cell cytolytic function. In patients with acute coronary syndromes (ACS), CD4(+)CD28(nul)l T cells express killer immunoglobulin-like receptors (KIRs). KIRs encompass a polymorphic family of receptors that recognize HLA class I molecules and have been implicated in self-tolerance. CD4(+)CD28(null) T-cell clones from patients with ACS and age-matched controls were compared for their KIR-expression profile. T-cell clones derived from the patients expressed a broader spectrum of KIRs (P<0.001) with preference for the stimulatory variant, CD158j. Additionally, CD4(+) T-cell clones from patients but not those from controls acquired de novo expression of the DAP12 molecule, an adapter chain that transmits CD158j-derived signals. Cumulative expression of CD158j and DAP12 endowed cytolytic competence on CD4(+)CD28(null) T cells, allowing them to kill in the absence of T-cell receptor triggering. Our data demonstrate that CD4(+)CD28(null) T cells in ACS are characterized by a unique gene expression profile. Consequently, these T cells acquire cytolytic capability that can bypass the need for T-cell receptor triggering and, thus, impose a threat to self-tolerance.