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Infect. Immun. doi:10.1128/IAI.00624-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Impaired expression of perforin and granulysin in CD8+ T cells at the site of infection in human chronic pulmonary tuberculosis

Center for Infectious Medicine (CIM), F59, Dept. of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden; Division of Infectious Diseases, I63, Dept. of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden

^* To whom correspondence should be addressed. Email: susanna.grundstrom{at}ki.se.

	Abstract

Protective immunity in tuberculosis is dependent on the coordinated release of cytolytic effector molecules from effector T cells and subsequent granule-associated killing of infected target cells. In this study, we investigated the expression of cytolytic (perforin, granzyme A) and antimicrobial (granulysin) molecules at the single cell level in cryopreserved lung tissue from patients with chronic, progressive tuberculosis disease. Quantification of protein expressing cells was performed by in situ imaging, while mRNA levels in the infected tissue were analyzed by real time PCR. Persistent inflammation, including excessive expression of inducible nitric oxide synthase (iNOS) in CD68+ macrophages and a significant infiltration of CD3+, CD8+ and CD4+ T cells, were evident in tuberculosis lesions in all patients. However, despite the accumulation of CD3+ T cells, perforin and granulysin expressing CD3+ T cells were detected at a 2-3 fold lower ratios in the tuberculosis lesions as compared to distal lung parenchyma and uninfected control lung, respectively. This was evident both at protein and mRNA level. Moreover, perforin and granulysin expressing CD8+ T cells were scarce in individual granulomas within the tuberculosis lesions. In contrast, a significant up-regulation of granzyme A expressing CD3+ T cells was evident in the lesions from all patients. Confocal microscopy revealed co-expression of perforin and granulysin, primarily in CD8+ T cells, however, this expression was lower in the TB lesions. These findings suggest that symptomatic, chronic tuberculosis disease is associated with an insufficient up-regulation of perforin and granulysin co-expression in CD8+ T cells at the local site of infection.