Department of Microbiology and Physiological Systems
Immunity | Immunology of Infectious Disease | Immunopathology | Pathogenic Microbiology
The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRβ bias. Using a retrogenic model of TB10.44-11-specific CD8+ T cells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-γ production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.
T cells, Cytotoxic T cells, Mycobacterium tuberculosis, Sequence motif analysis, Granulomas, Immune response, Tuberculosis, Protein sequencing
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Copyright: © 2015 Nunes-Alves et al.
DOI of Published Version
Nunes-Alves C, Booty MG, Carpenter SM, Rothchild AC, Martin CJ, Desjardins D, Steblenko K, Kløverpris HN, Madansein R, Ramsuran D, Leslie A, Correia-Neves M, Behar SM. Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection. PLoS Pathog. 2015 May 6;11(5):e1004849. doi: 10.1371/journal.ppat.1004849. eCollection 2015 May. PubMed PMID: 25945999; PubMed Central PMCID: PMC4422591. Link to article on publisher's website
Nunes-Alves, Claudio; Booty, Matthew G.; Carpenter, Stephen M.; Rothchild, Alissa C.; Martin, Constance J.; Desjardins, Danielle; Steblenko, Katherine; Kløverpris, Henrik N.; Madansein, Rajhmun; Ramsuran, Duran; Leslie, Alasdair; Correia-Neves, Margarida; and Behar, Samuel M., "Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection" (2015). Microbiology and Physiological Systems Publications and Presentations. 13.
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