Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection
Authors
Nunes-Alves, ClaudioBooty, 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
Behar, Samuel M.
UMass Chan Affiliations
Department of Microbiology and Physiological SystemsDocument Type
Journal ArticlePublication Date
2015-05-06Keywords
T cellsCytotoxic T cells
Mycobacterium tuberculosis
Sequence motif analysis
Granulomas
Immune response
Tuberculosis
Protein sequencing
Immunity
Immunology of Infectious Disease
Immunopathology
Pathogenic Microbiology
Metadata
Show full item recordAbstract
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.Source
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
DOI
10.1371/journal.ppat.1004849Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36449PubMed ID
25945999Notes
Data Availability: The data files for this study are publicly deposited in the University of Massachusetts Medical School’s institutional repository, eScholarship@UMMS. The permanent link to the data is http://dx.doi.org/10.13028/M2WC7N.
Republished, corrected article from 17 September 2015 uploaded 22 October 2015.
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Copyright: © 2015 Nunes-Alves et al.