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Mycobacterium Tuberculosis Activation Following Stimulation by T Cell + Differential Gene Expression Identifies Novel Markers of CD4 + and CD8+ T Cell Activation Following Stimulation by Mycobacterium tuberculosis This information is current as of September 23, 2021. Jacqueline M. Cliff, Iryna N. J. Andrade, Rohit Mistry, Christopher L. Clayton, Mark G. Lennon, Alan P. Lewis, Ken Duncan, Pauline T. Lukey and Hazel M. Dockrell J Immunol 2004; 173:485-493; ; doi: 10.4049/jimmunol.173.1.485 Downloaded from http://www.jimmunol.org/content/173/1/485 Supplementary http://www.jimmunol.org/content/suppl/2004/06/17/173.1.485.DC1 http://www.jimmunol.org/ Material References This article cites 51 articles, 20 of which you can access for free at: http://www.jimmunol.org/content/173/1/485.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential Gene Expression Identifies Novel Markers of CD4؉ and CD8؉ T Cell Activation Following Stimulation by Mycobacterium tuberculosis1 Jacqueline M. Cliff,2* Iryna N. J. Andrade,* Rohit Mistry,†‡ Christopher L. Clayton,† Mark G. Lennon,† Alan P. Lewis,† Ken Duncan,† Pauline T. Lukey,† and Hazel M. Dockrell* T cell activation in response to antigenic stimulation is a complex process, involving changes in the expression level of a large number of genes. We have used cDNA array technology to characterize the differences in gene expression between human CD4؉ and CD8؉ T cells. PBMC from six healthy donors were stimulated with live Mycobacterium tuberculosis, and the gene expression profiles of each donor’s CD4؉ and CD8؉ T cells were analyzed separately. ANOVA revealed 518 genes that were consistently ؉ ؉ differentially expressed between CD4 and CD8 T cells. These differentially expressed genes include a combination of well- Downloaded from known, previously characterized genes with a range of biological functions and unknown in silico predicted hypothetical genes. Where possible, the novel genes have been characterized using bioinformatics, and putative transcription factors, signaling mol- ecules, transmembrane, and secreted factors have been identified. A subset of these differentially expressed genes could be ex- ploited as markers of CD4؉ and CD8؉ T cell activation for use in vaccine trials. These observed differences in the gene expression profile of CD4؉ and CD8؉ T cells following activation by a human pathogen contribute to an increased understanding of T cell activation and differentiation and the roles these T cell subsets may play in immunity to infection. The Journal of Immunology, http://www.jimmunol.org/ 2004, 173: 485–493. hen a T cell is stimulated by encountering an APC levels of thousands of genes simultaneously, and can be used to expressing its cognate Ag, many biological processes identify differentially expressed genes in different cell types or W occur, including metabolic activation, morphological tissues. They have been successfully used in the analysis of various changes, proliferation, and differentiation into distinct effector and aspects of T cell function, including T cell activation in vivo in memory cells. These processes are mediated in part by alterations response to staphylococcal enterotoxin B (2) and determination of in gene expression levels, and these changes are affected by co- the gene expression profile of suppressor T cells in mice (3, 4). In stimulation via cytokine receptors and accessory and adhesion human T cells, the genetic profiles of type 1 and 2 CD4ϩ and by guest on September 23, 2021 molecules, as well as the signals emanating from TCR triggering. CD8ϩ T cells have been characterized (5, 6), and the effects of CD4ϩ and CD8ϩ T cells are phenotypically similar, and both sub- signaling through the IL-2R (7) and members of the CD28 family sets respond to antigenic stimulation in a similar manner. Indeed, (8, 9) on TCR signaling have been determined. activated CD4ϩ and CD8ϩ T cells can both be induced to differ- To date, there has not been a systematic array-based analysis of entiate into either type 1 or 2 cells, secreting similar patterns of the differences in gene expression profiles of human CD4ϩ and cytokines (1). The main difference between the two T cell subsets CD8ϩ T cells following physiological Ag-specific stimulation. is their distinct roles in protective immunity, as effector CD8ϩ T This study addresses this issue by investigation of effector CD4ϩ cells recognize and destroy infected host cells by recognizing en- and CD8ϩ T cells specific for a relevant human pathogen, Myco- dogenous peptides presented by MHC class I, whereas effector bacterium tuberculosis, which leads to 8 million new cases of tu- CD4ϩ T cells recognize exogenous peptides presented via MHC berculosis (TB)3 disease and 2 million deaths each year (10). The class II and provide help to other immune cells. These differences efficacy of the currently available vaccine against M. tuberculosis, in effector CD4ϩ and CD8ϩ T cells must be reflected in differences Mycobacterium bovis bacillus Calmette-Guerin (BCG), has been in the gene expression profile of the two T cell types. variable in trials with ϳ80% observed protection against adult pul- High density cDNA and oligonucleotide microarray hybridiza- monary TB in the United Kingdom, but much lower protection tion technologies can be used to measure the mRNA expression demonstrated in large parts of the world, including SubSaharan Africa and Southeast Asia (11). The pivotal role of CD4ϩ T cells in protection against TB is clearly demonstrated by the suscepti- *Department of Infectious and Tropical Diseases, London School of Hygiene & Trop- † bility of HIV/AIDS patients to develop TB disease, and this cor- ical Medicine, London, United Kingdom; GlaxoSmithKline Research and Develop- ϩ ment, Stevenage, United Kingdom; and ‡Medical Research Council Centre for relates with the decline in CD4 T cell count. In mice, Ab-medi- ϩ Molecular & Cellular Studies, University of Stellenbosch, Cape Town, South Africa ated depletion of CD4 T cells results in rapid reactivation of a ϩ Received for publication November 18, 2003. Accepted for publication April persistent TB infection (12). Effector CD4 T cells are recruited 14, 2004. to infected lungs, where they secrete TNF-␣ and IFN-␥, leading to The costs of publication of this article were defrayed in part by the payment of page activation of the infected alveolar macrophages, enabling them to charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was funded by the GlaxoSmithKline Action TB Initiative. 2 Address correspondence and reprint requests to Dr. Jacqueline M. Cliff, Department 3 Abbreviations used in this paper: TB, tuberculosis; BCG, bacillus Calmette-Guerin; of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, DAP10, DNAX activation protein 10; ESTs, expressed sequence tags; MOI, multi- London, WC1E 7HT, U.K. E-mail address: [email protected] plicity of infection; PPD, purified protein derivative; qRT-PCR, quantitative RT-PCR. Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 486 NOVEL MARKERS OF CD4ϩ AND CD8ϩ T CELL ACTIVATION ϩ kill the mycobacteria (13). A CD8 T cell response is also nec- [3H]thymidine (Amersham Biosciences, Bucks, U.K.) was added. Points ␤ shown represent the means of quadruplicate measurements for each donor. essary for immunity. 2-microglobulin-deficient mice, which lack ϩ functional CD8 T cells, are highly susceptible to M. tuberculosis IFN-␥ ELISA (14), and these cells appear to play a crucial role in the latent phase PBMC were incubated at 1 ϫ 106/ml and stimulated with PPD or M. bovis of infection (15). In human TB patients, healthy contacts, and ϩ BCG, and supernatants were collected on day 6. Quadruplicate superna- BCG-vaccinated donors, CD8 T cells reactive against a number tants were pooled and assayed in duplicate by sandwich ELISA, using a ϩ of mycobacterial Ags have been identified (16, 17). Such CD8 T matched Ab pair and rIFN-␥ standard purchased from BD PharMingen cells produce IFN-␥ and TNF-␣ (18) and are cytolytic for infected (San Diego, CA). ϩ monocyte-derived macrophages (19). Furthermore, these CD8 T Differential gene expression cells secrete granulysin, which, in conjunction with perforin, can Generation of nylon cDNA arrays, synthesis of 33P-labeled cDNA complex directly kill the M. tuberculosis bacillus within a macrophage (20). ϩ probes, and hybridization of complex probes to the arrays were performed, Cytotoxic CD4 T cells can also be generated by M. tuberculosis as previously described (26). cDNA arrays were synthesized from a nor- ϩ stimulation. However, the kinetics of CD4 T cell-mediated killing malized leukocyte cDNA library derived from five normal healthy donors, are different from those of CD8ϩ T cells, occurring after 16 h rather which was purchased from Invitrogen Life Technologies (Renfrewshire, than 4 h following antigenic stimulation in vitro (21). The control of U.K.). The library was normalized so that the redundancy was reduced, and therefore the representation of low level-expressed genes, such as cytokine cytolytic function in the two cell types is therefore different, and may and receptor genes, was enhanced (Invitrogen sales literature), allowing as be reflected in differences in the expression level of certain genes.
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