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

• Published in: PLoS pathogens Vol. 12; no. 1; p. e1005380
• Main Authors: Carpenter, Stephen M, Nunes-Alves, Cláudio, Booty, Matthew G, Way, Sing Sing, Behar, Samuel M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2016; Public Library of Science (PLoS)
• Subjects: Adoptive Transfer; Animals; Antibiotics; Antigens; CD8-Positive T-Lymphocytes - immunology; Cell Separation; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Experiments; Flow Cytometry; Funding; High-Throughput Nucleotide Sequencing; Immunologic Memory - immunology; Infections; Institutional repositories; Lymphocyte Activation - immunology; Lymphocytes; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Pathogens; Receptors, Antigen, T-Cell - immunology; T cell receptors; Tuberculosis; Tuberculosis - immunology; Tuberculosis Vaccines - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1005380

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.