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Preferential escape of subdominant CD8+ T cells during negative selection results in an altered antiviral T cell hierarchy
Authors:Slifka Mark K  Blattman Joseph N  Sourdive David J D  Liu Fei  Huffman Donald L  Wolfe Tom  Hughes Anna  Oldstone Michael B A  Ahmed Rafi  Von Herrath Matthias G
Institution:Oregon Health and Science University Vaccine and Gene Therapy Institute, Beaverton, OR 97006, USA.
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.
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