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TitleA higher activation threshold of memory CD8+ T cells has a fitness cost that is modified by TCR affinity during Tuberculosis
Author(s)Carpenter, Stephen M
Nunes-Alves, Cláudio
Booty, Matthew G
Way, Sing Sing
Behar, Samuel M
KeywordsAdoptive Transfer
CD8-Positive T-Lymphocytes
Cell Separation
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
High-Throughput Nucleotide Sequencing
Immunologic Memory
Lymphocyte Activation
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Receptors, Antigen, T-Cell
Tuberculosis Vaccines
Issue dateJan-2016
PublisherPublic Library of Science
JournalPLoS Pathogens
CitationCarpenter SM, Nunes-Alves C, Booty MG, Way SS, Behar SM (2016) A higher activation threshold of memory CD8+ T cells has a fitness cost that is modified by TCR affinity during Tuberculosis. PLoSPathog12(1):e1005380. doi:10.1371/journal.ppat.1005380
Abstract(s)T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.
DescriptionAll relevant data are within the paper and its Supporting Information files except for the primary TCR sequences. The data files for the primary TCR sequences are publicly deposited in the University of Massachusetts Medical School’s institutional repository, eScholarship@UMMS. The permanent link to the data is
Publisher version
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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