Transcriptional Profile of Tuberculosis Antigen–Specific T Cells Reveals Novel Multifunctional Features

In latent tuberculosis infection (LTBI) spread of the bacteria is contained by a persistent immune response, which includes CD4+ T cells as important contributors. In this study we show that TB-specific CD4+ T cells have a characteristic chemokine expression signature (CCR6+CXCR3+CCR4−), and that the overall number of these cells is significantly increased in LTBI donors compared with healthy subjects. We have comprehensively characterized the transcriptional signature of CCR6+CXCR3+CCR4− cells and found significant differences to conventional Th1, Th17, and Th2 cells, but no major changes between healthy and LTBI donors. CCR6+CXCR3+CCR4− cells display lineage-specific signatures of both Th1 and Th17 cells, but also have a unique gene expression program, including genes associated with susceptibility to TB, enhanced T cell activation, enhanced cell survival, and induction of a cytotoxic program akin to CTL cells. Overall, the gene expression signature of CCR6+CXCR3+CCR4− cells reveals characteristics important for controlling latent TB infections.

[1]  Paul Theodor Pyl,et al.  HTSeq—a Python framework to work with high-throughput sequencing data , 2014, bioRxiv.

[2]  Paul Theodor Pyl,et al.  HTSeq – A Python framework to work with high-throughput sequencing data , 2014 .

[3]  Andrea De Maria,et al.  Immunology of Tuberculosis , 2014, Mediterranean journal of hematology and infectious diseases.

[4]  Mark S. Sundrud,et al.  Pro-inflammatory human Th17 cells selectively express P-glycoprotein and are refractory to glucocorticoids , 2014, The Journal of experimental medicine.

[5]  Michael Levin,et al.  Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study , 2013, PLoS medicine.

[6]  V. Pascual,et al.  Transcriptional Blood Signatures Distinguish Pulmonary Tuberculosis, Pulmonary Sarcoidosis, Pneumonias and Lung Cancers , 2013, PloS one.

[7]  G. Guzzetta,et al.  The Roles of Immune Memory and Aging in Protective Immunity and Endogenous Reactivation of Tuberculosis , 2013, PloS one.

[8]  S. Vigano,et al.  Lack of Mycobacterium tuberculosis–specific interleukin‐17A–producing CD4+ T cells in active disease , 2013, European journal of immunology.

[9]  D. Littman,et al.  Harnessing CD4+ T cell responses in HIV vaccine development , 2013, Nature Medicine.

[10]  K. Honda,et al.  Transcriptional Reprogramming of Mature CD4+ T helper Cells generates distinct MHC class II-restricted Cytotoxic T Lymphocytes , 2013, Nature Immunology.

[11]  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.

[12]  R. Djukanović,et al.  An integrated nano-scale approach to profile miRNAs in limited clinical samples. , 2012, American journal of clinical and experimental immunology.

[13]  J. Wolchok,et al.  Induction of tumoricidal function in CD4+ T cells is associated with concomitant memory and terminally differentiated phenotype , 2012, The Journal of experimental medicine.

[14]  V. Pascual,et al.  Detectable Changes in The Blood Transcriptome Are Present after Two Weeks of Antituberculosis Therapy , 2012, PloS one.

[15]  Philip E. Bourne,et al.  Immune epitope database analysis resource , 2012, Nucleic Acids Res..

[16]  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.

[17]  Stefan H. E. Kaufmann,et al.  Common patterns and disease-related signatures in tuberculosis and sarcoidosis , 2012, Proceedings of the National Academy of Sciences.

[18]  D. Jarrossay,et al.  Pathogen-induced human TH17 cells produce IFN-γ or IL-10 and are regulated by IL-1β , 2012, Nature.

[19]  E. Rosenberg,et al.  HIV-Specific Cytolytic CD4 T Cell Responses During Acute HIV Infection Predict Disease Outcome , 2012, Science Translational Medicine.

[20]  D. Mager,et al.  Human Th1 and Th17 Cells Exhibit Epigenetic Stability at Signature Cytokine and Transcription Factor Loci , 2011, The Journal of Immunology.

[21]  Dirk Repsilber,et al.  Functional Correlations of Pathogenesis-Driven Gene Expression Signatures in Tuberculosis , 2011, PloS one.

[22]  Mingxia Zhang,et al.  An SNP selection strategy identified IL-22 associating with susceptibility to tuberculosis in Chinese , 2011, Scientific reports.

[23]  Vijay K. Kuchroo,et al.  Cutting Edge: TIGIT Has T Cell-Intrinsic Inhibitory Functions , 2011, The Journal of Immunology.

[24]  R. Rabin,et al.  CCR2 Identifies a Stable Population of Human Effector Memory CD4+ T Cells Equipped for Rapid Recall Response , 2010, The Journal of Immunology.

[25]  Stuart Adams,et al.  Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment , 2010, Proceedings of the National Academy of Sciences.

[26]  R. Wilkinson,et al.  Polyfunctional T cells in human tuberculosis , 2010, European journal of immunology.

[27]  T. Mcclanahan,et al.  Human Th17 Cells Comprise Heterogeneous Subsets Including IFN-γ–Producing Cells with Distinct Properties from the Th1 Lineage , 2010, The Journal of Immunology.

[28]  Virginia Pascual,et al.  An Interferon-Inducible Neutrophil-Driven Blood Transcriptional Signature in Human Tuberculosis , 2010, Nature.

[29]  W. Huber,et al.  which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. MAnorm: a robust model for quantitative comparison of ChIP-Seq data sets , 2011 .

[30]  J. Routy,et al.  Peripheral Blood CCR4CCR6 and CXCR3CCR6 CD4 T Cells Are Highly Permissive to HIV-1 Infection , 2010 .

[31]  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.

[32]  F. Sallusto,et al.  Heterogeneity of CD4+ memory T cells: Functional modules for tailored immunity , 2009, European journal of immunology.

[33]  F. Sallusto,et al.  Human naive and memory CD4+ T cell repertoires specific for naturally processed antigens analyzed using libraries of amplified T cells , 2009, The Journal of experimental medicine.

[34]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[35]  Lior Pachter,et al.  Sequence Analysis , 2020, Definitions.

[36]  Terence P. Speed,et al.  A single-sample method for normalizing and combining full-resolution copy numbers from multiple platforms, labs and analysis methods , 2009, Bioinform..

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

[38]  J. Hamilton.  Colony-stimulating factors in inflammation and autoimmunity , 2008, Nature Reviews Immunology.

[39]  I. Orme,et al.  Relative Levels of M-CSF and GM-CSF Influence the Specific Generation of Macrophage Populations during Infection with Mycobacterium tuberculosis1 , 2008, The Journal of Immunology.

[40]  L. Cosmi,et al.  Phenotypic and functional features of human Th17 cells , 2007, The Journal of experimental medicine.

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

[42]  E. N. Miller,et al.  Evidence for a cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians , 2004, Genes and Immunity.

[43]  P. Schneider,et al.  BAFF AND APRIL: a tutorial on B cell survival. , 2003, Annual review of immunology.

[44]  A. Silman,et al.  British Society for Rheumatology Biologics Register , 2003, Annals of the rheumatic diseases.

[45]  S. Kaufmann,et al.  Protection against tuberculosis: cytokines, T cells, and macrophages , 2002, Annals of the rheumatic diseases.

[46]  J. Casanova,et al.  Genetic dissection of immunity to mycobacteria: the human model. , 2002, Annual review of immunology.

[47]  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.

[48]  Joseph Keane,et al.  Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent , 2001 .

[49]  J. Flynn,et al.  Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[50]  L. Ashman,et al.  Expression of c-Kit and functional drug efflux are correlated in de novo acute myeloid leukaemia , 1997, Leukemia.

[51]  J. Nemunaitis,et al.  Macrophage function activating cytokines: potential clinical application. , 1993, Critical reviews in oncology/hematology.

[52]  I. Roninson,et al.  Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells , 1991, Cell.