Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection

Abstract

Mycobacterium tuberculosis (MTB)-specific cytokine responses in the peripheral blood and at the site of infection may differ significantly within the same individual, but the underlying T-cell subset changes are largely unknown. Here, we measured effector and memory T-cell markers on CD4 + T cells (CD45RO, cysteine chemokine receptor (CCR)7, and CD27) in peripheral blood and at the site of active tuberculosis (TB). Additionally, T cells were stimulated overnight with purified protein derivative (PPD) and early secretory antigenic target (ESAT)-6 to determine which T-cell subset produces MTB-specific interferon (IFN)-γ. A striking decrease in CCR7 and CD27 expression on T cells was noted at the site of active TB. Likewise, IFN-γ expressing, ESAT-6 specific CD4 + CD45RO + CD27 − T cells were dramatically increased at the site of infection but were not detectable in peripheral blood. An antigen-specific expansion of differentiated T cells at the site of active TB infection was poorly reflected in peripheral blood. Insight in these changes in MTB-specific effector T cells in different compartments of the body could lead to new approaches for immune-based diagnosis and interventions. Keywords: effector T cell r memory T cell r tuberculosis See accompanying Commentary by Lange and Sester IntroductionActive tuberculosis (TB) is characterized by the expansion of Mycobacterium tuberculosis (MTB)-specific T cells at the site of infection [1,2]. The MTB-specific T-cell response in peripheral blood reflects only in part the immune response at the site of infection [1][2][3].Correspondence: Prof. Stefan Winkler e-mail: stefan.winkler@meduniwien.ac.at Many different T-cell surface proteins are used to discriminate various T-cell subsets. The cysteine chemokine receptor (CCR)7 has been shown to be necessary for cell extravasation through high endothelial venules in T-cell areas of secondary lymphoid organs and has been utilized together with CD45RO to specify so-called central memory T cells, which are known to be enriched in lymph nodes and tonsils in humans [4]. Conversely, the lack of CCR7 on the surface of T cells has been used to identify "effector memory" T cells [4]. CD27, a tumor necrosis factor (TNF)-receptor-family member, is expressed by naïve CD4 + T cells and is irreversibly lost after repeated T-cellwww.eji-journal.eu Eur. J. Immunol. 2012. 42: 2844-2850 HIGHLIGHTS 2845 Figure 1. Representative dot plots of T cells from blood and site of disease. Peripheral blood and pleural fluid T cells were isolated and stained with CD4, CD45RO, CCR7, and CD27. The frequency of CD4 + , CD4 + CD45RO + , and CD4 + CD45RO − T cells expressing CCR7 and CD27, respectively, of a patient suffering from TB and a patient suffering from non-TB diseases are shown. The dot plots are representative of six patients suffering from TB and seven patients with non-TB diseases. Measurements were performed in duplicates.receptor engagement, marking thus T-cell maturation and acquisition of antigen specificity [5]. CD45RO has been linked to a memo...

Immune activation and regulatory T cells in Mycobacterium tuberculosis infected lymph nodes

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Gene expression profiling identifies candidate biomarkers for active and latent tuberculosis

“…These genes were NEMF (nuclear export mediator factor), ASUN (asunder spermatogenesis regulator), and DHX29 (DEAH (Asp-Glu-Ala-His) box polypeptide 29). Then, we selected PTPRC (protein tyrosine phosphatase, receptor type, C) or CD45, an estalished marker of active TB [ 21 ], as a reference standard.…”

Rapid diagnosis of pulmonary tuberculosis by combined molecular and immunological methods

“…Following contact with antigen-presenting cells, M. tuberculosis-specific T-cells clonally expand in regional lymph nodes and migrate to the site of the infection where they differentiate into effector T-cells [6][7][8]. After loss of special phenotypical T-cell surface markers, these cell populations are probably unable to re-enter the bloodstream and become enriched at the site of disease [9,10]. In contrast to detection of M. tuberculosis-specific effector T-cells in peripheral blood, detection of M. tuberculosis-specific effector T-cells by the interferon (IFN)-γ release assay at the site of the infection has a high diagnostic accuracy for active TB even when AFB and M. tuberculosis DNA are not detectable from local samples such as bronchoalveolar lavage (BAL) [11][12][13][14][15], pleural fluid [16,17], pericardial fluid [18], cerebrospinal fluid [19] or ascites [20].…”