Abstract
Negative selection is designed to purge the immune system of high-avidity, self-reactive T cells and thereby protect the host from overt autoimmunity. In this in vivo viral infection model, we show that there is a previously unappreciated dichotomy involved in negative selection in which high-avidity CD8(+) T cells specific for a dominant epitope are eliminated, whereas T cells specific for a subdominant epitope on the same protein preferentially escape deletion. Although this resulted in significant skewing of immunodominance and a substantial depletion of the most promiscuous T cells, thymic and/or peripheral deletion of high-avidity CD8(+) T cells was not accompanied by any major change in the TCR V beta gene family usage or an absolute deletion of a single preferred complementarity-determining region 3 length polymorphism. This suggests that negative selection allows high-avidity CD8(+) T cells specific for subdominant or cryptic epitopes to persist while effectively deleting high-avidity T cells specific for dominant epitopes. By allowing the escape of subdominant T cells, this process still preserves a relatively broad peripheral TCR repertoire that can actively participate in antiviral and/or autoreactive immune responses.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antigens, Differentiation, T-Lymphocyte / biosynthesis
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology*
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Clonal Deletion / genetics
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Clonal Deletion / immunology*
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Cytotoxicity, Immunologic / genetics
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Epitopes, T-Lymphocyte / immunology*
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Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
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Immunodominant Epitopes / immunology*
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Lymphocyte Activation / genetics
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Lymphocytic choriomeningitis virus / immunology
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Multigene Family / immunology
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Nucleoproteins / biosynthesis
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Nucleoproteins / genetics
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Receptors, Antigen, T-Cell, alpha-beta / biosynthesis
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / virology
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Viral Proteins / biosynthesis
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Viral Proteins / genetics
Substances
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Antigens, Differentiation, T-Lymphocyte
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Epitopes, T-Lymphocyte
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Immunodominant Epitopes
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Nucleoproteins
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Receptors, Antigen, T-Cell, alpha-beta
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Viral Proteins