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A higher activation threshold of memory CD8+ T cells has a fitness cost that is modified by TCR affinity during Tuberculosis

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Summary: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.
Main Authors:Carpenter, Stephen M
Other Authors:Nunes-Alves, Cláudio; Booty, Matthew G; Way, Sing Sing; Behar, Samuel M
Subject:Adoptive Transfer Animals CD8-Positive T-Lymphocytes Cell Separation Disease Models, Animal Enzyme-Linked Immunosorbent Assay Flow Cytometry High-Throughput Nucleotide Sequencing Immunologic Memory Lymphocyte Activation Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Receptors, Antigen, T-Cell Tuberculosis Tuberculosis Vaccines
Year:2016
Country:Portugal
Document type:article
Access type:open access
Associated institution:Universidade do Minho
Language:English
Origin:RepositóriUM - Universidade do Minho

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