Carpenter, Stephen M.Nunes-Alves, CláudioBooty, Matthew GregoryWay, Sing SingBehar, Samuel M.2016-02-012016Carpenter, Stephen M., Cláudio Nunes-Alves, Matthew G. Booty, Sing Sing Way, and Samuel M. Behar. 2016. “A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.” PLoS Pathogens 12 (1): e1005380. doi:10.1371/journal.ppat.1005380. http://dx.doi.org/10.1371/journal.ppat.1005380.1553-7366http://nrs.harvard.edu/urn-3:HUL.InstRepos:24983862T 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.en-USJournal Article2016-02-0110.1371/journal.ppat.1005380