title: 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 alphabeta 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 beta-chain CDR3-length distribution analysis using PCR primers specific for 23 Vbeta families performed in eight individuals with CAS affecting tri- or bileaflet aortic valves revealed considerable oligoclonal T cell expansion. In five cases, beta-chain nucleotide sequencing in five selected Vbeta 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 x 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 beta-chain CDR3 regions were homologous to TCR beta-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 alphabeta T cells are implicated in mediating a component of the valvular injury responsible for CAS.
authors.affiliation: Division of Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: Henry D
authors.initials: HD
authors.lastname: Wu
authors.forename: Mathew S
authors.initials: MS
authors.lastname: Maurer
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.forename: Charles C
authors.initials: CC
authors.lastname: Marboe
authors.forename: Elena M
authors.initials: EM
authors.lastname: Ruiz-Vazquez
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Ramakrishnan
authors.forename: Allan
authors.initials: A
authors.lastname: Schwartz
authors.forename: M David
authors.initials: MD
authors.lastname: Tilson
authors.forename: Allan S
authors.initials: AS
authors.lastname: Stewart
authors.forename: Robert
authors.initials: R
authors.lastname: Winchester
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001024:Aortic Valve Stenosis / Q000276:immunology* / Q000473:pathology; D002114:Calcinosis / Q000276:immunology* / Q000473:pathology; D022801:Complementarity Determining Regions; D005260:Female; D019674:Genes, T-Cell Receptor beta; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry*; D017385:Sequence Homology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D022801:Complementarity Determining Regions; D016693:Receptors, Antigen, T-Cell, alpha-beta