title: Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection.
abstract: The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRβ bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-γ production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.
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: 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, 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; Program in Immunology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Alissa C
authors.initials: AC
authors.lastname: Rothchild
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.
authors.forename: Constance J
authors.initials: CJ
authors.lastname: Martin
authors.affiliation: Division of Infectious Disease, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Danielle
authors.initials: D
authors.lastname: Desjardins
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Steblenko
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa; Nelson Mandela School of Medicine, University of Kwa-Zulu-Natal, Durban, South Africa; Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Henrik N
authors.initials: HN
authors.lastname: Kløverpris
authors.affiliation: Nelson Mandela School of Medicine, University of Kwa-Zulu-Natal, Durban, South Africa.
authors.forename: Rajhmun
authors.initials: R
authors.lastname: Madansein
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa.
authors.forename: Duran
authors.initials: D
authors.lastname: Ramsuran
authors.affiliation: KwaZulu-Natal Research Institute for TB and HIV, Durban, South Africa; Nelson Mandela School of Medicine, University of Kwa-Zulu-Natal, Durban, South Africa.
authors.forename: Alasdair
authors.initials: A
authors.lastname: Leslie
authors.affiliation: 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: Margarida
authors.initials: M
authors.lastname: Correia-Neves
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: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*; D032581:Tuberculosis Vaccines / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma