Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis

Robert Winchester, Margrit Wiesendanger, Will O'Brien, Hui Zhu Zhang, Mathew S. Maurer, Linda Gillam, Allan Schwartz, Charles Marboe, Allan S. Stewart

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR β-chain length and sequence analysis we confirmed that the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR+ activated CD8 cells and in the CD8+CD28nullCD57+ memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4+CD28 null T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28null, and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28nullCD8+ T cells and to a lesser degree in the CD8+CD28+ subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion, and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve.

Original languageEnglish (US)
Pages (from-to)1006-1014
Number of pages9
JournalJournal of Immunology
Volume187
Issue number2
DOIs
StatePublished - Jul 15 2011
Externally publishedYes

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Tricuspid Valve
Mitral Valve
T-Lymphocytes
Clone Cells
Bicuspid
Calcification of Aortic Valve
Null Lymphocytes
Adaptive Immunity
HLA-DR Antigens
Aortic Valve
Sequence Analysis
Flow Cytometry
Phenotype

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Winchester, Robert ; Wiesendanger, Margrit ; O'Brien, Will ; Zhang, Hui Zhu ; Maurer, Mathew S. ; Gillam, Linda ; Schwartz, Allan ; Marboe, Charles ; Stewart, Allan S. / Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. In: Journal of Immunology. 2011 ; Vol. 187, No. 2. pp. 1006-1014.
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abstract = "We sought to delineate further the immunological significance of T lymphocytes infiltrating the valve leaflets in calcific aortic stenosis (CAS) and determine whether there were associated alterations in circulating T cells. Using clonotypic TCR β-chain length and sequence analysis we confirmed that the repertoire of tricuspid CAS valves contains numerous expanded T cell clones with varying degrees of additional polyclonality, which was greatest in cases with severe calcification. We now report a similar proportion of clonal expansions in the much younger bicuspid valve CAS cases. Peripheral blood flow cytometry revealed elevations in HLA-DR+ activated CD8 cells and in the CD8+CD28nullCD57+ memory-effector subset that were significantly greater in both bicuspid and tricuspid CAS cases with more severe valve calcification. Lesser increases of CD4+CD28 null T cells were identified, principally in cases with concurrent atherosclerotic disease. Upon immunostaining the CD8 T cells in all valves were mainly CD28null, and CD8 T cell percentages were greatest in valves with oligoclonal repertoires. T cell clones identified by their clonotypic sequence as expanded in the valve were also found expanded in the circulating blood CD28nullCD8+ T cells and to a lesser degree in the CD8+CD28+ subset, directly supporting the relationship between immunologic events in the blood and the valve. The results suggest that an ongoing systemic adaptive immune response is occurring in cases with bicuspid and tricuspid CAS, involving circulating CD8 T cell activation, clonal expansion, and differentiation to a memory-effector phenotype, with trafficking of T cells in expanded clones between blood and the valve.",
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Circulating activated and effector memory T cells are associated with calcification and clonal expansions in bicuspid and tricuspid valves of calcific aortic stenosis. / Winchester, Robert; Wiesendanger, Margrit; O'Brien, Will; Zhang, Hui Zhu; Maurer, Mathew S.; Gillam, Linda; Schwartz, Allan; Marboe, Charles; Stewart, Allan S.

In: Journal of Immunology, Vol. 187, No. 2, 15.07.2011, p. 1006-1014.

Research output: Contribution to journalArticle

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AU - Winchester, Robert

AU - Wiesendanger, Margrit

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