title: Patients with tuberculosis disease have Mycobacterium tuberculosis-specific CD8 T cells with a pro-apoptotic phenotype and impaired proliferative capacity, which is not restored following treatment.
abstract: CD8 T cells play a critical role in control of chronic viral infections; however, the role of these cells in containing persistent bacterial infections, such as those caused by Mycobacterium tuberculosis (Mtb), is less clear. We assessed the phenotype and functional capacity of CD8 T cells specific for the immunodominant Mtb antigens CFP-10 and ESAT-6, in patients with pulmonary tuberculosis (TB) disease, before and after treatment, and in healthy persons with latent Mtb infection (LTBI). In patients with TB disease, CFP-10/ESAT-6-specific IFN-γ+ CD8 T cells had an activated, pro-apoptotic phenotype, with lower Bcl-2 and CD127 expression, and higher Ki67, CD57, and CD95 expression, than in LTBI. When CFP-10/ESAT-6-specific IFN-γ+ CD8 T cells were detectable, expression of distinct combinations of these markers was highly sensitive and specific for differentiating TB disease from LTBI. Successful treatment of disease resulted in changes of these markers, but not in restoration of CFP-10/ESAT-6-specific CD8 or CD4 memory T cell proliferative capacity. These data suggest that high mycobacterial load in active TB disease is associated with activated, short-lived CFP-10/ESAT-6-specific CD8 T cells with impaired functional capacity that is not restored following treatment. By contrast, LTBI is associated with preservation of long-lived CFP-10/ESAT-6-specific memory CD8 T cells that maintain high Bcl-2 expression and which may readily proliferate.
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America; Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Noella D
authors.initials: ND
authors.lastname: Moshi
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Abrahams
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Michele
authors.initials: M
authors.lastname: van Rooyen
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Terrence
authors.initials: T
authors.lastname: O'rie
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Marwou
authors.initials: M
authors.lastname: de Kock
authors.affiliation: South African Tuberculosis Vaccine Initiative (SATVI) and School of Child and Adolescent Health, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000942:Antigens, Bacterial / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology / Q000378:metabolism; D018959:CD57 Antigens / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D019394:Ki-67 Antigen / Q000276:immunology / Q000378:metabolism; D055985:Latent Tuberculosis / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology; D055815:Young Adult; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D018959:CD57 Antigens; C117940:CFP-10 protein, Mycobacterium tuberculosis; C093276:ESAT-6 protein, Mycobacterium tuberculosis; D053699:Interleukin-7 Receptor alpha Subunit; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D019014:fas Receptor; D007371:Interferon-gamma
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