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      Identification of Mycobacterium tuberculosis-Specific Th1, Th17 and Th22 Cells Using the Expression of CD40L in Tuberculous Pleurisy


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          Important advances have been made in the immunodiagnosis of tuberculosis (TB) based on the detection of Mycobacterium tuberculosis (MTB)-specific T cells. However, the sensitivity and specificity of the immunological approach are relatively low because there are no specific markers for antigen-specific Th cells, and some of the Th cells that do not produce cytokines can be overlooked using this approach. In this study, we found that MTB-specific peptides of ESAT-6/CFP-10 can stimulate the expression of CD40L specifically in CD4 + T cells but not other cells from pleural fluid cells (PFCs) in patients with tuberculous pleurisy (TBP). CD4 +CD40L + but not CD4 +CD40L T cells express IFN-γ, IL-2, TNF-α, IL-17 or IL-22 after stimulation with MTB-specific peptides. In addition, CD4 +CD40L + T cells were found to be mostly polyfunctional T cells that simultaneously produce IFN-γ, IL-2 and TNF-α and display an effector or effector memory phenotype (CD45RA CD45RO +CCR7 CD62L ICOS ). To determine the specificity of CD4 +CD40L + T cells, we incubated PFCs with ESTA-6/CFP-10 peptides and sorted live CD4 +CD40L + and CD4 +CD40L T cells by flow cytometry. We further demonstrated that sorted CD4 +CD40L +, but not CD4 +CD40L fractions, principally produced IFN-γ, IL-2, TNF-α, IL-17 and IL-22 following restimulation with ESTA-6/CFP-10 peptides. Taken together, our data indicate that the expression of CD40L on MTB-specific CD4 + T cells could be a good marker for the evaluation and isolation of MTB-specific Th cells and might also be useful in the diagnosis of TB.

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          IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge.

          Interferon-gamma is key in limiting Mycobacterium tuberculosis infection. Here we show that vaccination triggered an accelerated interferon-gamma response by CD4(+) T cells in the lung during subsequent M. tuberculosis infection. Interleukin 23 (IL-23) was essential for the accelerated response, for early cessation of bacterial growth and for establishment of an IL-17-producing CD4(+) T cell population in the lung. The recall response of the IL-17-producing CD4(+) T cell population occurred concurrently with expression of the chemokines CXCL9, CXCL10 and CXCL11. Depletion of IL-17 during challenge reduced the chemokine expression and accumulation of CD4(+) T cells producing interferon-gamma in the lung. We propose that vaccination induces IL-17-producing CD4(+) T cells that populate the lung and, after challenge, trigger the production of chemokines that recruit CD4(+) T cells producing interferon-gamma, which ultimately restrict bacterial growth.
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            Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research.

            Until recently, the tuberculin skin test was the only test for detecting latent tuberculosis (TB) infection, but 2 ex vivo interferon-gamma release assays (IGRAs) are now commercially licensed. To estimate sensitivity, specificity, and reproducibility of IGRAs (commercial or research versions of QuantiFERON [QFT] and Elispot) for diagnosing latent TB infection in healthy and immune-suppressed persons. The authors searched MEDLINE and reviewed citations of all original articles and reviews for studies published in English. Studies had evaluated IGRAs using Mycobacterium tuberculosis-specific antigens (RD1 antigens) and overnight (16- to 24-h) incubation times. Reference standards had to be clearly defined without knowledge of test results. DATA EXTRACTION AND QUALITY ASSESSMENT: Specific criteria for quality assessment were developed for sensitivity, specificity, and reproducibility. When newly diagnosed active TB was used as a surrogate for latent TB infection, sensitivity of all tests was suboptimal, although it was higher with Elispot. No test distinguishes active TB from latent TB. Sensitivity of the tuberculin skin test and IGRAs was similar in persons who were categorized into clinical gradients of exposure. Pooled specificity was 97.7% (95% CI, 96% to 99%) and 92.5% (CI, 86% to 99%) for QFT and for Elispot, respectively. Both assays were more specific than the tuberculin skin test in samples vaccinated with bacille Calmette-Guérin. Elispot was more sensitive than the tuberculin skin test in 3 studies of immune-compromised samples. Discordant tuberculin skin test and IGRA reactions were frequent and largely unexplained, although some may be related to varied definitions of positive test results. Reversion of IGRA results from positive to negative was common in 2 studies in which it was assessed. Most studies used cross-sectional designs with the inherent limitation of no gold standard for latent TB infection, and most involved small samples with a widely varying likelihood of true-positive and false-positive test results. There is insufficient evidence on IGRA performance in children, immune-compromised persons, and the elderly. New IGRAs show considerable promise and have excellent specificity. Additional studies are needed to better define their performance in high-risk populations and in serial testing. Longitudinal studies are needed to define the predictive value of IGRAs.
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              CD40-CD40 ligand.

              CD40 is a cell surface receptor that belongs to the tumor necrosis factor-R (TNF-R) family, and that was first identified and functionally characterized on B lymphocytes. Its critical role in T cell-dependent humoral immune responses was demonstrated by patients with the hyper-IgM syndrome, as well as by gene targeting in mice. However, in recent years it has become clear that CD40 is expressed much more broadly, including expression on monocytes, dendritic cells, endothelial cells, and epithelial cells. In addition, the CD40-ligand (CD40-L/CD154), a member of the TNF family, is also expressed more widely than activated CD4+ T cells only. Therefore it is now thought that CD40-CD40-L interactions play a more general role in immune regulation. Collectively these studies have culminated in pre-clinical and clinical studies that are in progress. This article reviews recent developments in this field of research, with main emphasis on (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types; and (4) in vivo functions of CD40/CD40-L interactions.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                18 May 2011
                : 6
                : 5
                : e20165
                [1 ]Institute of Immunology, Zhongshan School of Medicine, Key Laboratory of Tropical Disease Control Research of Ministry of Education, Sun Yat-sen University, Guangzhou, People's Republic of China
                [2 ]Chest Hospital of Guangzhou, Guangzhou, People's Republic of China
                French National Centre for Scientific Research, France
                Author notes

                Conceived and designed the experiments: CW. Performed the experiments: LL DQ. Analyzed the data: LL. Contributed reagents/materials/analysis tools: DQ XF. Wrote the paper: LL. Recruited all subjects: SL XZ.

                Li et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                : 1 February 2011
                : 14 April 2011
                Page count
                Pages: 8
                Research Article
                Anatomy and Physiology
                Immune Physiology
                Immune Cells
                T Cells
                Infectious Diseases
                Bacterial Diseases



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