A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis

PLoS Pathogens

Sing Sing Way¹  Stephen M. Carpenter¹  Matthew G. Booty²  Cláudio Nunes-Alves³  Samuel M. Behar⁴ 

[1] Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America;Division of Infectious Disease, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America;Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

关键词: T cells;    Cytotoxic T cells;    Memory T cells;    Mycobacterium tuberculosis;    Vaccination;    immunization;    Blood;    Vaccines;    Cloning;   

DOI  :  10.1371/journal.ppat.1005380

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY