Preferential Escape of Subdominant CD8+ T Cells During Negative Selection Results in an Altered Antiviral T Cell Hierarchy

• Published in: The Journal of immunology (1950) 2003-02, Vol.170 (3), p.1231-1239
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Differentiation, T-Lymphocyte - biosynthesis; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Cell Differentiation - genetics; Cell Differentiation - immunology; Clonal Deletion - genetics; Clonal Deletion - immunology; Cytotoxicity, Immunologic - genetics; Epitopes, T-Lymphocyte - immunology; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Immunodominant Epitopes - immunology; Lymphocyte Activation - genetics; Lymphocytic choriomeningitis virus - immunology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Multigene Family - immunology; Nucleoproteins - biosynthesis; Nucleoproteins - genetics; Receptors, Antigen, T-Cell, alpha-beta - biosynthesis; Receptors, Antigen, T-Cell, alpha-beta - genetics; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - virology; Viral Proteins - biosynthesis; Viral Proteins - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.3.1231

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.