UMMS Affiliation

Department of Microbiology and Physiological Systems; Division of Infectious Diseases and Immunology, Department of Medicine

Date

1-8-2016

Document Type

Article

Disciplines

Immunity | Immunology of Infectious Disease | Immunopathology | Immunoprophylaxis and Therapy | Pathogenic Microbiology

Abstract

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.

Rights and Permissions

Citation: 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

Comments

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.

Data Availability: All 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 http://dx.doi.org/10.13028/M2CC70

Related Resources

Link to article in PubMed

Keywords

T cells, Cytotoxic T cells, Memory T cells, Mycobacterium tuberculosis, Vaccination and immunization

PubMed ID

26745507

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

 
 

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