The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells

Abstract

Valve lesions in degenerative calcific aortic stenosis (CAS), a disorder affecting 3% of those older than 75 years, are infiltrated by T lymphocytes. We sought to determine whether the αβ TCR repertoire of these valve-infiltrating lymphocytes exhibited features either of a polyclonal nonselective response to inflammation or contained expanded clones suggesting a more specific immune process. TCR β-chain CDR3-length distribution analysis using PCR primers specific for 23 Vβ families performed in eight individuals with CAS affecting tri- or bileaflet aortic valves revealed considerable oligoclonal T cell expansion. In five cases, β-chain nucleotide sequencing in five selected Vβ families showed that an average of 92% of the valve-infiltrating T cell repertoire consisted of expanded T cell clones, differing markedly in composition from the relatively more polyclonal peripheral CD8 or CD4 T cell subsets found even in this elderly population. Twenty-four of the valve-infiltrating T cell clones also had the same clone identified in blood, some of which were highly expanded. Interestingly, 22 of these 24 shared clones were CD8 in lineage (p = 1.5 × 10−12), suggesting a possible relationship to the expanded CD8+CD28− T cell clones frequently present in the elderly. Additionally, the sequences of several TCR β-chain CDR3 regions were homologous to TCR β-chains identified previously in allograft arteriosclerosis. We infer that these findings are inconsistent with a nonselective secondary response of T cells to inflammation and instead suggest that clonally expanded αβ T cells are implicated in mediating a component of the valvular injury responsible for CAS.