Background: Rupture of atherosclerotic plaque is the most common cause of acute coronary syndrome (ACS with ruptured fibrous cap, RFC-ACS). In about one third of ACS-events, however, the causative acute pathology is plaque erosion, characterized by coronary thrombus formation at a culprit plaque with intact fibrous cap (IFC-ACS). The pathomechanism of this important pathology is largely unknown. Within the translational OPTICO-ACS study program, we recently observed significant enrichment of cytotoxic- and helper T-cells selectively at the culprit lesion site of IFC-ACS, but phenotypical and functional details of the observed T-cell response remain unknown.  

Methods and results: In a delicate balance, the principal CD4⁺ T-helper (T_H)-subsets (regulatory T-cells (T_regs, CD127_lo,CD25⁺), T_H1- (CXCR3⁺), T_H2- (CCR4⁺CCR6^-), T_H17- (CCR4⁺CCR6⁺), T_H9- (CCR4^-CCR6⁺) and T-follicular helper (T_FH, CXCR5⁺) cells) mediate distinct pro-inflammatory, destabilizing (e.g. T_H1, T_H17) or anti-inflammatory, protective (e.g. T_reg, T_H2) effects on coronary atherosclerosis. For in depth characterization of local adaptive immune processes in IFC- and RFC-ACS, we used a novel combination of OCT imaging, catheter-based sample acquisition and flow-cytometry in a preliminary cohort of 17 ACS patients. Pointing to a favorable immune profile in IFC-ACS, we showed markedly elevated T_reg/T_H1, T_reg/T_H17 and T_H2/T_H1 ratios (p ≤0.01), as well as a trend towards local T_reg accumulation ((p=0.053) as % total CD4⁺ T-cells in whole blood aspirated from the culprit lesion site) in IFC-ACS as compared to RFC-ACS. Interestingly, cytotoxic T-cells at the culprit lesion site of IFC-, but not RFC-ACS showed enhanced (p<0.01) expression of exhaustion markers (CD8⁺PD1⁺CD57⁺). In RFC-ACS, in contrast, T_H1 and T_H17 cells were significantly enriched (p ≤0.03) and we observed selective expansion of a highly differentiated cytotoxic CD8/CD28^null-subset with high effector potential despite a replicative senescence. There were no significant differences in the T_H9 or T_FH subsets and CD4⁺ memory distribution was comparable among both ACS-causing pathologies.

Summary: For the first time, this study presents detailed phenotypic and functional characterization of the CD4⁺ and CD8⁺ T-cell response in different pathophysiologies of ACS. Besides the quantitative enrichment of T-cells previously described within IFC-ACS, culprit lesions with intact fibrous cap host a favorable, T_reg-dominated adaptive response as compared to a skew towards aggressive T-effector phenotypes in RFC-ACS.