Adaptive CX3CR1-defined cd8 t-cell remodelling in non-ischaemic dilated cardiomyopathy
V Jeyalan, L Debois, K Bennaceur, S Cookson, L Borg, E Michaelsson, G Foldes, T Williams, M McCorkindale, R Maier, L Chang, B Beaver, S Plein, D Austin, I SpyridopoulosAbstract
Background
Immune involvement in non-ischaemic dilated cardiomyopathy (DCM) is incompletely understood, and it remains unclear whether chronic disease is characterised by immune activation, depletion, or adaptive remodelling.
Purpose
To define longitudinal immune kinetics in DCM and determine their relationship to myocardial fibrosis assessed by cardiac magnetic resonance (CMR).
Methods
We performed prospective longitudinal immune phenotyping in 100 patients with non-ischaemic DCM (90 with 6-month follow-up). Absolute leukocyte and lymphocyte subset counts were quantified using TruCount flow cytometry. Multi-parameter flow cytometry characterised CX3CR1-defined CD8 T-cell states, and CX3CR1 expression intensity was assessed by mean fluorescence intensity. Single-cell RNA sequencing of sorted CD8 T cells was performed in a stratified subset with participant-level pseudobulk differential expression. Baseline CMR included late gadolinium enhancement (LGE), ventricular volumes, strain, and parametric mapping.
Results
At baseline, LGE-positive patients demonstrated more advanced ventricular remodelling (left ventricular ejection fraction 38% vs 44%, p=0.011; global longitudinal strain −12.15% vs −15.10%, p=0.006; left ventricular end-systolic volume index 61.8 vs 49.8 ml/m², p=0.007), without differences in T1, T2, or extracellular volume. Over 6 months, modest reductions in absolute lymphocyte subsets occurred in LGE-negative patients (CD8 median change −37.5 cells/µL, p=0.008), whereas counts were preserved in LGE-positive disease; neutrophils and monocytes remained stable in both strata. Despite divergent absolute kinetics, compositional remodelling was conserved across fibrosis strata, including reduced non-classical monocyte proportions and increased classical monocytes. Within CD8 T cells, terminally differentiated effector memory (TEMRA) proportions increased in both LGE-negative and LGE-positive patients (median change +2.8% and +4.5%, respectively), accompanied by redistribution from CX3CR1⁺CD28⁻ toward CX3CR1⁻CD28⁺ TEMRA states (both p<0.01). CX3CR1 expression intensity was preserved across most lymphoid subsets, with selective reduction confined to CD8 TEMRA cells in LGE-negative disease. Transcriptomic analysis identified a CX3CR1-associated programme characterised by reduced cytotoxic effector gene expression and altered proximal signalling pathways.
Conclusions
Chronic DCM demonstrates LGE-dependent immune kinetics and a conserved CX3CR1-defined CD8 phenotypic remodelling programme culminating in expansion of CX3CR1-negative TEMRA states. These findings support a model of adaptive immune recalibration rather than ongoing myocardial inflammation or immune depletion in established disease.