Department of Microbiology and Physiological Systems; Division of Infectious Diseases and Immunology, Department of Medicine
Immunity | Immunology of Infectious Disease | Immunopathology | Immunoprophylaxis and Therapy | Pathogenic Microbiology
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.
T cells, Cytotoxic T cells, Memory T cells, Mycobacterium tuberculosis, Vaccination and immunization
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Copyright: © 2016 Carpenter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Carpenter SM, Nunes-Alves C, Booty MG, Way SS, Behar SM. A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis. PLoS Pathog. 2016 Jan 8;12(1):e1005380. doi:10.1371/journal.ppat.1005380. eCollection 2016 Jan. PubMed PMID: 26745507; PubMed Central PMCID: PMC4706326. Link to article on publisher's website
Carpenter, Stephen M.; Nunes-Alves, Claudio; Booty, Matthew G.; Way, Sing Sing; and Behar, Samuel M., "A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis" (2016). Microbiology and Physiological Systems Publications and Presentations. 15.
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