Antigens for CD4 and CD8 T cells in tuberculosis.

Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (MTB), represents an important cause of morbidity and mortality worldwide for which an improved vaccine and immunodiagnostics are urgently needed. CD4(+) and CD8(+) T cells play an important role in host defense to TB. Definition of the antigens recognized by these T cells is critical for improved understanding of the immunobiology of TB and for development of vaccines and diagnostics. Herein, the antigens and epitopes recognized by classically HLA class I- and II-restricted CD4(+) and CD8(+) T cells in humans infected with MTB are reviewed. Immunodominant antigens and epitopes have been defined using approaches targeting particular TB proteins or classes of proteins and by genome-wide discovery approaches. Antigens and epitopes recognized by classically restricted CD4(+) and CD8(+) T cells show extensive breadth and diversity in MTB-infected humans.

[1]  M. Alderson,et al.  Mycobacterium tuberculosis-specific CD8+ T cells preferentially recognize heavily infected cells. , 2003, American journal of respiratory and critical care medicine.

[2]  J. Flynn,et al.  An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection , 1993, The Journal of experimental medicine.

[3]  J. Flynn,et al.  Immunology of tuberculosis. , 2003, Annual review of immunology.

[4]  M. Maeurer,et al.  Human Leukocyte Antigens A*3001 and A*3002 Show Distinct Peptide-Binding Patterns of the Mycobacterium tuberculosis Protein TB10.4: Consequences for Immune Recognition , 2010, Clinical and Vaccine Immunology.

[5]  Alessandro Sette,et al.  Conserved hepatitis C virus sequences are highly immunogenic for CD4+ T cells: Implications for vaccine development , 1999, Hepatology.

[6]  J. Casanova,et al.  Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. , 1998, Science.

[7]  J. Zeng,et al.  A proteome-scale identification of novel antigenic proteins in Mycobacterium tuberculosis toward diagnostic and vaccine development. , 2010, Journal of proteome research.

[8]  C. Kortsik,et al.  Impact of MHC class I alleles on the M. tuberculosis antigen-specific CD8+ T-cell response in patients with pulmonary tuberculosis , 2007, Genes and Immunity.

[9]  C. Harding,et al.  Roles of proteasomes, transporter for antigen presentation (TAP), and beta 2-microglobulin in the processing of bacterial or particulate antigens via an alternate class I MHC processing pathway. , 1996, Journal of immunology.

[10]  L. McCue,et al.  Identification and Characterization of Mycobacterial Proteins Differentially Expressed under Standing and Shaking Culture Conditions, Including Rv2623 from a Novel Class of Putative ATP-Binding Proteins , 2001, Infection and Immunity.

[11]  I. Orme,et al.  Protection against Mycobacterium tuberculosis infection by adoptive immunotherapy. Requirement for T cell-deficient recipients , 1983, The Journal of experimental medicine.

[12]  P. Andersen,et al.  Tuberculosis vaccine development. , 2002, Current opinion in pulmonary medicine.

[13]  J. Bennedsen,et al.  Proteins released from Mycobacterium tuberculosis during growth , 1991, Infection and immunity.

[14]  John Sidney,et al.  Identification and Antigenicity of Broadly Cross-Reactive and Conserved Human Immunodeficiency Virus Type 1-Derived Helper T-Lymphocyte Epitopes , 2001, Journal of Virology.

[15]  C. Dye.  Global epidemiology of tuberculosis , 2006, The Lancet.

[16]  Paul D van Helden,et al.  Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions , 2006, BMC Evolutionary Biology.

[17]  S. Behar,et al.  Evasion of innate immunity by Mycobacterium tuberculosis: is death an exit strategy? , 2010, Nature Reviews Microbiology.

[18]  John Sidney,et al.  Rationally Engineered Therapeutic Proteins with Reduced Immunogenicity , 2005, The Journal of Immunology.

[19]  M. Horwitz,et al.  Immunization with extracellular proteins of Mycobacterium tuberculosis induces cell-mediated immune responses and substantial protective immunity in a guinea pig model of pulmonary tuberculosis , 1992, Infection and immunity.

[20]  H. Mollenkopf,et al.  Differential T cell responses to Mycobacterium tuberculosis ESAT6 in tuberculosis patients and healthy donors , 1998, European journal of immunology.

[21]  H. Dockrell,et al.  Human cytolytic and interferon gamma-secreting CD8+ T lymphocytes specific for Mycobacterium tuberculosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[22]  G. Schoolnik,et al.  An Unbiased Genome-Wide Mycobacterium tuberculosis Gene Expression Approach To Discover Antigens Targeted by Human T Cells Expressed during Pulmonary Infection , 2013, The Journal of Immunology.

[23]  Magdalini Moutaftsi,et al.  Selective CD4+ T cell help for antibody responses to a large viral pathogen: deterministic linkage of specificities. , 2008, Immunity.

[24]  Philip L Felgner,et al.  Dynamic antibody responses to the Mycobacterium tuberculosis proteome , 2010, Proceedings of the National Academy of Sciences.

[25]  P. Andersen,et al.  Human T-cell responses to secreted antigen fractions of Mycobacterium tuberculosis , 1995, Infection and immunity.

[26]  P. Andersen,et al.  TB subunit vaccines--putting the pieces together. , 2005, Microbes and infection.

[27]  J. Drijfhout,et al.  Double‐ and monofunctional CD4+ and CD8+ T‐cell responses to Mycobacterium tuberculosis DosR antigens and peptides in long‐term latently infected individuals , 2011, European journal of immunology.

[28]  B. Gicquel,et al.  Life on the inside: Probing Mycobacterium tuberculosis gene expression during infection , 2000, Immunology and cell biology.

[29]  P. Brennan,et al.  CD1-restricted T cell recognition of microbial lipoglycan antigens. , 1995, Science.

[30]  Ravi V. Kolla,et al.  T Cell Responses to Known Allergen Proteins Are Differently Polarized and Account for a Variable Fraction of Total Response to Allergen Extracts , 2012, The Journal of Immunology.

[31]  D. Woodland,et al.  Early T‐cell responses in tuberculosis immunity , 2008, Immunological reviews.

[32]  John Sidney,et al.  HLA-DR-Promiscuous T Cell Epitopes from Plasmodium falciparum Pre-Erythrocytic-Stage Antigens Restricted by Multiple HLA Class II Alleles1 2 , 2000, The Journal of Immunology.

[33]  John Sidney,et al.  A Systematic Assessment of MHC Class II Peptide Binding Predictions and Evaluation of a Consensus Approach , 2008, PLoS Comput. Biol..

[34]  C. Flory,et al.  Immunization of mice with mycobacterial culture filtrate proteins , 1992, Clinical and experimental immunology.

[35]  J. Belisle,et al.  Immunoproteomic Identification of Human T Cell Antigens of Mycobacterium tuberculosis That Differentiate Healthy Contacts from Tuberculosis Patients* , 2009, Molecular & Cellular Proteomics.

[36]  D. Snider,et al.  Tuberculosis in patients with human immunodeficiency virus infection. , 1991, The New England journal of medicine.

[37]  R. North,et al.  Immunity to tuberculosis. , 2003, Annual review of immunology.

[38]  Bjoern Peters,et al.  Molecular Determinants of T Cell Epitope Recognition to the Common Timothy Grass Allergen , 2010, The Journal of Immunology.

[39]  A. Krensky,et al.  Identification of epitopes of Mycobacterium tuberculosis 16-kDa protein recognized by human leukocyte antigen-A*0201 CD8(+) T lymphocytes. , 2002, The Journal of infectious diseases.

[40]  S. Sampson,et al.  Mycobacterial PE/PPE Proteins at the Host-Pathogen Interface , 2011, Clinical & developmental immunology.

[41]  J. Routy,et al.  Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T Cells Are Highly Permissive to HIV-1 Infection , 2009, The Journal of Immunology.

[42]  G. Schoolnik,et al.  Immunogenicity of Novel DosR Regulon-Encoded Candidate Antigens of Mycobacterium tuberculosis in Three High-Burden Populations in Africa , 2009, Clinical and Vaccine Immunology.

[43]  J. Flynn,et al.  Major histocompatibility complex class I-restricted T cells are required for resistance to Mycobacterium tuberculosis infection. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[44]  G. Besra,et al.  CD1c-mediated T-cell recognition of isoprenoid glycolipids in Mycobacterium tuberculosis infection , 2000, Nature.

[45]  N. Ariel,et al.  Whole genome identification of Mycobacterium tuberculosis vaccine candidates by comprehensive data mining and bioinformatic analyses , 2008, BMC Medical Genomics.

[46]  D. Sherman,et al.  Human Mycobacterium tuberculosis CD8 T Cell Antigens/Epitopes Identified by a Proteomic Peptide Library , 2013, PloS one.

[47]  F. Oftung,et al.  Multiple epitopes from the Mycobacterium tuberculosis ESAT-6 antigen are recognized by antigen-specific human T cell lines. , 2000, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[48]  M. Maeurer,et al.  Extensive major histocompatibility complex class I binding promiscuity for Mycobacterium tuberculosis TB10.4 peptides and immune dominance of human leucocyte antigen (HLA)‐B*0702 and HLA‐B*0801 alleles in TB10.4 CD8+ T‐cell responses , 2010, Immunology.

[49]  J. Drijfhout,et al.  Identification of Human T-Cell Responses to Mycobacterium tuberculosis Resuscitation-Promoting Factors in Long-Term Latently Infected Individuals , 2011, Clinical and Vaccine Immunology.

[50]  J. Flynn,et al.  CD8+ T cells in tuberculosis. , 2002, American journal of respiratory and critical care medicine.

[51]  Peter Andersen,et al.  Specific T-Cell Epitopes for Immunoassay-Based Diagnosis of Mycobacterium tuberculosis Infection , 2004, Journal of Clinical Microbiology.

[52]  D. Havlir,et al.  Tuberculosis in patients with human immunodeficiency virus infection. , 1999, The New England journal of medicine.

[53]  I. Orme,et al.  T cell response to Mycobacterium tuberculosis. , 1993, The Journal of infectious diseases.

[54]  S. Reed,et al.  Tuberculosis vaccine development; from mouse to man. , 2005, Microbes and infection.

[55]  D E Snider,et al.  Global epidemiology of tuberculosis. Morbidity and mortality of a worldwide epidemic. , 1995, JAMA.

[56]  P. Klenerman,et al.  Direct Ex Vivo Analysis of Antigen-Specific IFN-γ-Secreting CD4 T Cells in Mycobacterium tuberculosis-Infected Individuals: Associations with Clinical Disease State and Effect of Treatment1 , 2001, The Journal of Immunology.

[57]  S. Kaufmann,et al.  Potential of novel Mycobacterium tuberculosis infection phase-dependent antigens in the diagnosis of TB disease in a high burden setting , 2012, BMC Infectious Diseases.

[58]  G. Ireton,et al.  Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis1 , 2008, The Journal of Immunology.

[59]  I. Orme,et al.  The application of proteomics in defining the T cell antigens of Mycobacterium tuberculosis , 2001, Proteomics.

[60]  H. Wiker,et al.  Isolation and partial characterization of major protein antigens in the culture fluid of Mycobacterium tuberculosis , 1991, Infection and immunity.

[61]  P. Andersen,et al.  Evidence for occurrence of the ESAT-6 protein in Mycobacterium tuberculosis and virulent Mycobacterium bovis and for its absence in Mycobacterium bovis BCG , 1996, Infection and immunity.

[62]  G. Schoolnik,et al.  Comparative genomics of BCG vaccines by whole-genome DNA microarray. , 1999, Science.

[63]  P. Barnes,et al.  Human CD8+ T cells recognize epitopes of the 28‐kDa hemolysin and the 38‐kDa antigen of Mycobacterium tuberculosis , 2003, Journal of leukocyte biology.

[64]  S. Porcelli,et al.  Evasion and subversion of antigen presentation by Mycobacterium tuberculosis. , 2009, Tissue antigens.

[65]  P. Andersen,et al.  Efficient protection against Mycobacterium tuberculosis by vaccination with a single subdominant epitope from the ESAT‐6 antigen , 2000, European journal of immunology.

[66]  D. Jarrossay,et al.  Surface phenotype and antigenic specificity of human interleukin 17–producing T helper memory cells , 2007, Nature Immunology.

[67]  Bjoern Peters,et al.  Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed against Three Antigenic Islands and Largely Contained in a CXCR3+CCR6+ Th1 Subset , 2013, PLoS pathogens.

[68]  I. Orme,et al.  Adoptive protection of the Mycobacterium tuberculosis-infected lung. Dissociation between cells that passively transfer protective immunity and those that transfer delayed-type hypersensitivity to tuberculin. , 1984, Cellular immunology.

[69]  E. Engleman,et al.  CTL response to Mycobacterium tuberculosis: identification of an immunogenic epitope in the 19-kDa lipoprotein. , 1998, Journal of immunology.

[70]  R. Wilkinson,et al.  High frequencies of circulating IFN‐γ‐secreting CD8 cytotoxic T cells specific for a novel MHC class I‐restricted Mycobacterium tuberculosis epitope in M. tuberculosis‐infected subjects without disease , 2000 .

[71]  J. Bates.  Diagnosis of tuberculosis. , 1979, Chest.

[72]  D. Russell,et al.  Mycobacterial persistence: adaptation to a changing environment. , 2001, Trends in microbiology.

[73]  J. Yewdell,et al.  Immunodominance in major histocompatibility complex class I-restricted T lymphocyte responses. , 1999, Annual review of immunology.

[74]  J. Flynn,et al.  Lessons from experimental Mycobacterium tuberculosis infections. , 2006, Microbes and infection.

[75]  Ole Lund,et al.  Genome-Based In Silico Identification of New Mycobacterium tuberculosis Antigens Activating Polyfunctional CD8+ T Cells in Human Tuberculosis , 2011, The Journal of Immunology.

[76]  M. Horwitz,et al.  Protective immunity against tuberculosis induced by vaccination with major extracellular proteins of Mycobacterium tuberculosis. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[77]  P. Butcher,et al.  Differential expression of mycobacterial proteins following phagocytosis by macrophages. , 2001, Microbiology.

[78]  J. Pfeifer,et al.  Phagocytic processing of bacterial antigens for class I MHC presentation to T cells , 1993, Nature.

[79]  T. Ottenhoff,et al.  Immunogenicity of Eight Dormancy Regulon-Encoded Proteins of Mycobacterium tuberculosis in DNA-Vaccinated and Tuberculosis-Infected Mice , 2006, Infection and Immunity.

[80]  J. Heuser,et al.  Trafficking and Release of Mycobacterial Lipids from Infected Macrophages , 2000, Traffic.

[81]  Julie A McMurry,et al.  Epitope-driven TB vaccine development: a streamlined approach using immuno-informatics, ELISpot assays, and HLA transgenic mice. , 2007, Current molecular medicine.

[82]  Ravi V. Kolla,et al.  Analysis of T Cell Responses to the Major Allergens from German Cockroach: Epitope Specificity and Relationship to IgE Production , 2012, The Journal of Immunology.

[83]  Antigen discovery and tuberculosis vaccine development in the post-genomic era. , 2001 .

[84]  J. Flynn,et al.  The spectrum of latent tuberculosis: rethinking the biology and intervention strategies , 2009, Nature Reviews Microbiology.

[85]  P. Barnes,et al.  Characterization of a Mycobacterium tuberculosis Peptide That Is Recognized by Human CD4+ and CD8+ T Cells in the Context of Multiple HLA Alleles1 , 2004, The Journal of Immunology.

[86]  J. Flynn,et al.  Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. , 1999, Journal of immunology.

[87]  P. Andersen.  The T cell response to secreted antigens of Mycobacterium tuberculosis. , 1994, Immunobiology.

[88]  Robert J Wilkinson,et al.  Eliminating latent tuberculosis. , 2009, Trends in microbiology.

[89]  B. Barrell,et al.  Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence , 1998, Nature.

[90]  William N. Rom,et al.  HLA-A2-Restricted CD8+-Cytotoxic-T-Cell Responses to Novel Epitopes in Mycobacterium tuberculosis Superoxide Dismutase, Alanine Dehydrogenase, and Glutamine Synthetase , 2004, Infection and Immunity.

[91]  S. Kaufmann,et al.  Identification of T-Cell Antigens Specific for Latent Mycobacterium Tuberculosis Infection , 2009, PloS one.

[92]  G. Schoolnik,et al.  Human T-cell responses to 25 novel antigens encoded by genes of the dormancy regulon of Mycobacterium tuberculosis. , 2006, Microbes and infection.

[93]  S. Behar.  Antigen-specific CD8(+) T cells and protective immunity to tuberculosis. , 2013, Advances in experimental medicine and biology.

[94]  Matthew S. Cook,et al.  Human Mucosal Associated Invariant T Cells Detect Bacterially Infected Cells , 2010, PLoS biology.

[95]  D. Russell,et al.  Identification of Mycobacterial Surface Proteins Released into Subcellular Compartments of Infected Macrophages , 2000, Infection and Immunity.

[96]  L. Malone,et al.  CD8+ T cells provide an immunologic signature of tuberculosis in young children. , 2012, American journal of respiratory and critical care medicine.

[97]  T. Eguale,et al.  Human T cell responses to the ESAT-6 antigen from Mycobacterium tuberculosis. , 1999, The Journal of infectious diseases.

[98]  L. Kaer,et al.  Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[99]  J. Belisle,et al.  HLA-E–dependent Presentation of Mtb-derived Antigen to Human CD8+ T Cells , 2002, The Journal of experimental medicine.

[100]  R. G. Hewinson,et al.  Recognition of Mycobacterial Epitopes by T Cells across Mammalian Species and Use of a Program That Predicts Human HLA-DR Binding Peptides To Predict Bovine Epitopes , 2003, Infection and Immunity.

[101]  Tige R. Rustad,et al.  The Enduring Hypoxic Response of Mycobacterium tuberculosis , 2008, PloS one.

[102]  S. Kaufmann,et al.  Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis , 2003, Nature Medicine.

[103]  R. Coler,et al.  Identification of Mycobacterium tuberculosis vaccine candidates using human CD4+ T-cells expression cloning. , 2009, Vaccine.

[104]  A. Mustafa,et al.  HLA-DR Binding Prediction and Experimental Evaluation of T-Cell Epitopes of Mycolyl Transferase 85B (Ag85B), a Major Secreted Antigen of Mycobacterium tuberculosis , 2005, Medical Principles and Practice.

[105]  Alimuddin Zumla,et al.  A Broad Profile of Co-Dominant Epitopes Shapes the Peripheral Mycobacterium tuberculosis Specific CD8+ T-Cell Immune Response in South African Patients with Active Tuberculosis , 2013, PloS one.

[106]  S. Dorman,et al.  Interferon-γ and interleukin-12 pathway defects and human disease , 2000 .

[107]  D. Lewinsohn,et al.  Views of immunology: effector T cells , 2011, Immunological reviews.

[108]  Parissa Farnia,et al.  Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculosis or totally drug-resistant strains in iran. , 2009, Chest.

[109]  D. Lewinsohn,et al.  Co-dependents: MR1-restricted MAIT cells and their antimicrobial function , 2012, Nature Reviews Microbiology.

[110]  S. Gordon,et al.  Identification of Novel Mycobacterium tuberculosis Antigens with Potential as Diagnostic Reagents or Subunit Vaccine Candidates by Comparative Genomics , 2002, Infection and Immunity.

[111]  E. Grant,et al.  CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ alpha beta T cell pool. , 1999, Journal of immunology.

[112]  S. Kaufmann,et al.  Impaired resistance to Mycobacterium tuberculosis infection after selective in vivo depletion of L3T4+ and Lyt-2+ T cells , 1987, Infection and immunity.

[113]  D. Lewinsohn,et al.  The Mycobacterium tuberculosis Phagosome Is a HLA-I Processing Competent Organelle , 2009, PLoS pathogens.

[114]  E. Carter,et al.  Analyzing Mycobacterium tuberculosis proteomes for candidate vaccine epitopes. , 2005, Tuberculosis.

[115]  P. Hopewell.  Impact of human immunodeficiency virus infection on the epidemiology, clinical features, management, and control of tuberculosis. , 1992, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[116]  Rikke Louise Vinther Skjøt, Else Marie Agger, Peter Ande.  Antigen Discovery and Tuberculosis Vaccine Development in the Post-genomic Era , 2001 .

[117]  Matthew S. Cook,et al.  Immunodominant Tuberculosis CD8 Antigens Preferentially Restricted by HLA-B , 2007, PLoS pathogens.

[118]  S. Reed,et al.  Characterization of Human CD8+ T Cells Reactive with Mycobacterium tuberculosis–infected Antigen-presenting Cells , 1998, The Journal of experimental medicine.

[119]  J. Greenbaum,et al.  Dissecting Mechanisms of Immunodominance to the Common Tuberculosis Antigens ESAT-6, CFP10, Rv2031c (hspX), Rv2654c (TB7.7), and Rv1038c (EsxJ) , 2012, The Journal of Immunology.

[120]  D. Sherman,et al.  Hypoxia Induces an Immunodominant Target of Tuberculosis Specific T Cells Absent from Common BCG Vaccines , 2010, PLoS pathogens.

[121]  S. Vermund,et al.  A prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection. , 1989, The New England journal of medicine.

[122]  Yang Liu,et al.  Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages , 2003, The Journal of experimental medicine.

[123]  S. Porcelli,et al.  CD1c restricts responses of mycobacteria-specific T cells. Evidence for antigen presentation by a second member of the human CD1 family. , 1996, Journal of immunology.

[124]  John L. Johnson,et al.  Mycobacterium tuberculosis Specific CD8+ T Cells Rapidly Decline with Antituberculosis Treatment , 2013, PloS one.

[125]  Singh,et al.  Human T‐ and B‐Cell Reactivity to the 16 kDa α‐Crystallin Protein of Mycobacterium tuberculosis , 1998, Scandinavian journal of immunology.

[126]  R. Siezen,et al.  The ESAT-6 gene cluster of Mycobacterium tuberculosis and other high G+C Gram-positive bacteria , 2001, Genome Biology.

[127]  D. Crane,et al.  Stationary phase-associated protein expression in Mycobacterium tuberculosis: function of the mycobacterial alpha-crystallin homolog , 1996, Journal of bacteriology.

[128]  S. Behar,et al.  Eicosanoid pathways regulate adaptive immunity to Mycobacterium tuberculosis , 2010, Nature Immunology.

[129]  T. Ganz,et al.  An antimicrobial activity of cytolytic T cells mediated by granulysin. , 1998, Science.

[130]  J. Bayona,et al.  Multidrug-resistant and extensively drug-resistant tuberculosis: a threat to global control of tuberculosis , 2010, The Lancet.

[131]  R. Wilkinson,et al.  Conserved Immune Recognition Hierarchy of Mycobacterial PE/PPE Proteins during Infection in Natural Hosts , 2012, PloS one.

[132]  T. Ottenhoff,et al.  Analysis of Mycobacterium tuberculosis-Specific CD8 T-Cells in Patients with Active Tuberculosis and in Individuals with Latent Infection , 2009, PloS one.

[133]  John Sidney,et al.  Immunomic Analysis of the Repertoire of T-Cell Specificities for Influenza A Virus in Humans , 2008, Journal of Virology.

[134]  D. Russell,et al.  Mycobacterial surface moieties are released from infected macrophages by a constitutive exocytic event. , 2001, European journal of cell biology.

[135]  N. Chandra,et al.  A combined immuno-informatics and structure-based modeling approach for prediction of T cell epitopes of secretory proteins of Mycobacterium tuberculosis. , 2006, Microbes and infection.

[136]  H. Dockrell,et al.  Human CD8+ T Cells Specific forMycobacterium tuberculosis Secreted Antigens in Tuberculosis Patients and Healthy BCG-Vaccinated Controls in The Gambia , 2000, Infection and Immunity.

[137]  S. Reed,et al.  Classically Restricted Human CD8+ T Lymphocytes Derived from Mycobacterium tuberculosis-Infected Cells: Definition of Antigenic Specificity1 , 2001, The Journal of Immunology.

[138]  D. Lewinsohn,et al.  Role of CD8+ T lymphocytes in control of Mycobacterium tuberculosis infection. , 2005, Microbes and infection.

[139]  A. Casadevall,et al.  Mycobacteria release active membrane vesicles that modulate immune responses in a TLR2-dependent manner in mice. , 2011, The Journal of clinical investigation.

[140]  S. Hasnain,et al.  The PE/PPE multigene family codes for virulence factors and is a possible source of mycobacterial antigenic variation: perhaps more? , 2012, Biochimie.

[141]  T. Ottenhoff,et al.  Mapping immune reactivity toward Rv2653 and Rv2654: two novel low-molecular-mass antigens found specifically in the Mycobacterium tuberculosis complex. , 2004, The Journal of infectious diseases.

[142]  M. Brennan,et al.  PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX‐5 , 2009, Molecular microbiology.

[143]  Bjoern Peters,et al.  An analysis of the epitope knowledge related to Mycobacteria , 2007, Immunome research.

[144]  D. Lowrie,et al.  Protection against tuberculosis by passive transfer with T-cell clones recognizing mycobacterial heat-shock protein 65. , 1994, Immunology.

[145]  I. Orme.  The kinetics of emergence and loss of mediator T lymphocytes acquired in response to infection with Mycobacterium tuberculosis. , 1987, Journal of immunology.

[146]  T. Ottenhoff,et al.  Antigenic Equivalence of Human T-Cell Responses toMycobacterium tuberculosis-Specific RD1-Encoded Protein Antigens ESAT-6 and Culture Filtrate Protein 10 and to Mixtures of Synthetic Peptides , 2000, Infection and Immunity.

[147]  Alimuddin Zumla,et al.  The immunological footprint of Mycobacterium tuberculosis T-cell epitope recognition. , 2012, The Journal of infectious diseases.

[148]  Nagasuma Chandra,et al.  HLA‐A*0201‐restricted Cytotoxic T‐cell Epitopes in Three PE/PPE Family Proteins of Mycobacterium tuberculosis , 2008, Scandinavian journal of immunology.

[149]  W. Bishai,et al.  Regulation of virulence genes in Mycobacterium tuberculosis. , 2001, International journal of medical microbiology : IJMM.

[150]  A. Mustafa,et al.  ProPred analysis and experimental evaluation of promiscuous T-cell epitopes of three major secreted antigens of Mycobacterium tuberculosis. , 2006, Tuberculosis.

[151]  K. McAdam,et al.  Mycobacterium tuberculosis genome‐wide screen exposes multiple CD8+ T cell epitopes , 2005, Clinical and experimental immunology.

[152]  Y. Sasaki,et al.  Specific Detection of Tuberculosis Infection: An Interferon-γ–based Assay Using New Antigens , 2004 .

[153]  P. Andersen,et al.  Diagnosis of Tuberculosis Based on the Two Specific Antigens ESAT-6 and CFP10 , 2000, Clinical Diagnostic Laboratory Immunology.

[154]  I. Orme,et al.  Disseminated tuberculosis in interferon gamma gene-disrupted mice , 1993, The Journal of experimental medicine.

[155]  C. D’Santos,et al.  Membrane and membrane‐associated proteins in Triton X‐114 extracts of Mycobacterium bovis BCG identified using a combination of gel‐based and gel‐free fractionation strategies , 2008, Proteomics.

[156]  A. Hill,et al.  Enumeration of T cells specific for RD1-encoded antigens suggests a high prevalence of latent Mycobacterium tuberculosis infection in healthy urban Indians. , 2001, The Journal of infectious diseases.

[157]  R. Brosch,et al.  Strong immunogenicity and cross-reactivity of Mycobacterium tuberculosis ESX-5 type VII secretion: encoded PE-PPE proteins predicts vaccine potential. , 2012, Cell host & microbe.

[158]  C Oseroff,et al.  Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. , 1994, Immunity.

[159]  A. Cooper,et al.  Cell-mediated immune responses in tuberculosis. , 2009, Annual review of immunology.