title: A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.
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.
authors.affiliation: Department of Microbiology and Physiological Systems, 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.|Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Carpenter
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.|Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Cláudio
authors.initials: C
authors.lastname: Nunes-Alves
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.|Program in Immunology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Booty
authors.affiliation: Division of Infectious Diseases, Cincinnati Children's Hospital, Cincinnati, Ohio, United States of America.
authors.forename: Sing Sing
authors.initials: SS
authors.lastname: Way
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Behar
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D059014:High-Throughput Nucleotide Sequencing; D007156:Immunologic Memory / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D032581:Tuberculosis Vaccines