title: A Quantitative Analysis of Complexity of Human Pathogen-Specific CD4 T Cell Responses in Healthy M. tuberculosis Infected South Africans.
abstract: We performed a quantitative analysis of the HLA restriction, antigen and epitope specificity of human pathogen specific responses in healthy individuals infected with M. tuberculosis (Mtb), in a South African cohort as a test case. The results estimate the breadth of T cell responses for the first time in the context of an infection and human population setting. We determined the epitope repertoire of eleven representative Mtb antigens and a large panel of previously defined Mtb epitopes. We estimated that our analytic methods detected 50-75% of the total response in a cohort of 63 individuals. As expected, responses were highly heterogeneous, with responses to a total of 125 epitopes detected. The 66 top epitopes provided 80% coverage of the responses identified in our study. Using a panel of 48 HLA class II-transfected antigen-presenting cells, we determined HLA class II restrictions for 278 epitope/donor recognition events (36% of the total). The majority of epitopes were restricted by multiple HLA alleles, and 380 different epitope/HLA combinations comprised less than 30% of the estimated Mtb-specific response. Our results underline the complexity of human T cell responses at a population level. Efforts to capture and characterize this broad and highly HLA promiscuous Mtb-specific T cell epitope repertoire will require significant peptide multiplexing efforts. We show that a comprehensive "megapool" of Mtb peptides captured a large fraction of the Mtb-specific T cells and can be used to characterize this response.
authors.affiliation: La Jolla Institute for Allergy and Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America.
authors.forename: Cecilia S
authors.initials: CS
authors.lastname: Lindestam Arlehamn
authors.affiliation: La Jolla Institute for Allergy and Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America.
authors.forename: Denise M
authors.initials: DM
authors.lastname: McKinney
authors.affiliation: La Jolla Institute for Allergy and Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Carpenter
authors.affiliation: La Jolla Institute for Allergy and Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America.
authors.forename: Sinu
authors.initials: S
authors.lastname: Paul
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Virginie
authors.initials: V
authors.lastname: Rozot
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Edward
authors.initials: E
authors.lastname: Makgotlho
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Yolande
authors.initials: Y
authors.lastname: Gregg
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Michele
authors.initials: M
authors.lastname: van Rooyen
authors.affiliation: Department of Medicine, Division of Infectious Diseases, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Ernst
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Mark
authors.initials: M
authors.lastname: Hatherill
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Willem A
authors.initials: WA
authors.lastname: Hanekom
authors.affiliation: La Jolla Institute for Allergy and Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Scriba
authors.affiliation: La Jolla Institute for Allergy and Immunology, Department of Vaccine Discovery, La Jolla, California, United States of America.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
mesh_terms: D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006680:HLA Antigens; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000276:immunology; D013019:South Africa; D014376:Tuberculosis / Q000276:immunology*
chemical_list: D000942:Antigens, Bacterial; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; C072681:Mycobacterium tuberculosis antigens