Preferential escape of subdominant CD8+ T cells during negative selection results in an altered antiviral T cell hierarchy

Mark K. Slifka, Joseph N. Blattman, David J.D. Sourdive, Fei Liu, Donald L. Huffman, Tom Wolfe, Anna Hughes, Michael B.A. Oldstone, Rafi Ahmed, Matthias G. Von Herrath

    Research output: Contribution to journalArticle

    33 Scopus citations

    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 Vβ gene family usage of 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.

    Original languageEnglish (US)
    Pages (from-to)1231-1239
    Number of pages9
    JournalJournal of Immunology
    Volume170
    Issue number3
    DOIs
    StatePublished - Feb 1 2003

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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    Slifka, M. K., Blattman, J. N., Sourdive, D. J. D., Liu, F., Huffman, D. L., Wolfe, T., Hughes, A., Oldstone, M. B. A., Ahmed, R., & Von Herrath, M. G. (2003). Preferential escape of subdominant CD8+ T cells during negative selection results in an altered antiviral T cell hierarchy. Journal of Immunology, 170(3), 1231-1239. https://doi.org/10.4049/jimmunol.170.3.1231