Abstract
Rheumatoid arthritis (RA) is characterized by premature immune aging with accumulation of degenerate T cells deficient for CD28. Gene expression profiling of CD4(+)CD28(-) and CD4(+)CD28(+) T cells to discover disease-promoting activities of CD28(-) T cells identified expression of CD70 as a most striking difference. Hence, CD70 was significantly more expressed in CD4 T cells from RA patients compared with age-matched controls (p < 0.006). The underlying mechanism was a failure to repress CD70 expression after activation-dependent induction. This defect in RA was not related to differential promoter demethylation. CD70 on bystander CD4(+)CD28(-) T cells functioned by lowering the threshold for T cell activation; admixture of CD4(+)CD28(-) T cells augmented TCR-induced responses of autologous naive CD4(+)CD28(+) T cells, particularly of low-avidity T cells. The data support a model in which CD70 expressed on T cells causes degeneracy in T cell responses and undermines tolerance mechanisms that normally control T cell autoreactivity.
Publication types
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Clinical Trial
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Comparative Study
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Multicenter Study
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Research Support, N.I.H., Extramural
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Aging, Premature / genetics
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Aging, Premature / immunology
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Aging, Premature / pathology
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Arthritis, Rheumatoid / genetics
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Arthritis, Rheumatoid / immunology*
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Arthritis, Rheumatoid / metabolism
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Arthritis, Rheumatoid / pathology
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Autoimmunity / genetics
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Autoimmunity / immunology
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Bystander Effect / genetics
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Bystander Effect / immunology
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CD27 Ligand / biosynthesis
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CD27 Ligand / genetics
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CD27 Ligand / immunology*
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / pathology
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DNA Methylation
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Female
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Gene Expression Profiling
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Gene Expression Regulation / immunology*
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Humans
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Immune Tolerance / genetics
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Immune Tolerance / immunology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Male
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Middle Aged
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Models, Immunological*
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Promoter Regions, Genetic / genetics
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Promoter Regions, Genetic / immunology
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Receptors, Antigen, T-Cell / genetics
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Receptors, Antigen, T-Cell / immunology
Substances
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CD27 Ligand
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CD28 Antigens
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CD70 protein, human
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Receptors, Antigen, T-Cell