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The Lymphocytic Infiltration in Calcific Aortic Stenosis Predominantly Consists of Clonally Expanded T Cells¹

Henry D. Wu^*, Mathew S. Maurer^*, Richard A. Friedman, Charles C. Marboe, Elena M. Ruiz-Vazquez, Rajasekhar Ramakrishnan^¶, Allan Schwartz^*, M. David Tilson^||, Allan S. Stewart^|| and Robert Winchester^2,,

^* Division of Cardiology, Department of Biomedical Informatics, Department of Pathology, and Division of Autoimmune and Molecular Diseases, ^¶ Division of Biostatistics, and ^|| Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032

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 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 -chain CDR3-length distribution analysis using PCR primers specific for 23 V families performed in eight individuals with CAS affecting tri- or bileaflet aortic valves revealed considerable oligoclonal T cell expansion. In five cases, -chain nucleotide sequencing in five selected V 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 -chain CDR3 regions were homologous to TCR -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 T cells are implicated in mediating a component of the valvular injury responsible for CAS.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by U.S. Public Health Service Grants R01 HL084599 and U19 AI046132, a Clinical Associate Physician Award from the National Institutes of Health (M01RR00645), and the Victoria and Esther Aboodi Award (to H.D.W.). M.S.M. was supported by a career development award from National Institute on Aging (K23-AG00966-A1A).

² Address correspondence and reprint requests to Dr. Robert Winchester, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. E-mail address: rjw8{at}columbia.edu

³ Abbreviations used in this paper: CAS, calcific aortic stenosis; VEGF, vascular endothelial growth factor; PB, peripheral blood; BLAST, basic local alignment search tool; p-MHC, peptide-MHC; HTLV, human T cell leukemia virus.

⁴ The on-line version of this article contains supplemental material.