Human and murine clonal [CD8.sup.+] T cell expansions arise during tuberculosis because of TCR selection

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...

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Bibliographic Details
Published in:PLoS pathogens 2015-05, Vol.11 (5)
Main Authors: Nunes-Alves, Claudio, Booty, Matthew G, Carpenter, Stephen M, Rothchild, Alissa C, Martin, Constance J, Desjardins, Danielle, Steblenko, Katherine, Kloverpris, Henrik N, Madansein, Rajhmun, Ramsuran, Duran, Leslie, Alasdair, Correia-Neves, Margarida, Behar, Samuel M
Format: Article
Language:English
Subjects:
Cell interactions
Cloning
Genetic aspects
Health aspects
Identification and classification
T cells
Tuberculosis
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Summary: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.sup.+] 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.sup.+] T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine [CD8.sup.+] T cell response against M. tuberculosis is dominated by [TB10.4.sub.4-11]-specific T cells with extreme TCRp bias. Using a retrogenic model of [TB10.4.sub.4-11] - 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.sup.+] T cells mediate protection against tuberculosis, which requires interferon-Y production and TAP1dependent 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.
ISSN:1553-7366
1553-7374
DOI:10.1371/journal.ppat.1004849