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Infection and Immunity, November 2007, p. 5210-5222, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00624-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Impaired Expression of Perforin and Granulysin in CD8+ T Cells at the Site of Infection in Human Chronic Pulmonary Tuberculosis{triangledown}

Jan Andersson,1,2 Arina Samarina,1 Joshua Fink,1 Sayma Rahman,1 and Susanna Grundström1*

Center for Infectious Medicine (CIM), F59, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden,1 Division of Infectious Diseases, I63, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden2

Received 2 May 2007/ Returned for modification 8 June 2007/ Accepted 6 July 2007

Protective immunity in tuberculosis is dependent on the coordinated release of cytolytic effector molecules from effector T cells and the subsequent granule-associated killing of infected target cells. In this study, we investigated the expression of cytolytic (perforin and 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 in CD68+ macrophages and significant infiltration of CD3+, CD8+ and CD4+ T cells, was 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 two- to threefold-lower ratios in the tuberculosis lesions than in distal lung parenchyma and uninfected control lungs, respectively. This was evident at both the protein and mRNA levels. Moreover, perforin- and granulysin-expressing CD8+ T cells were scarce in individual granulomas within the tuberculosis lesions. In contrast, significant up-regulation of granzyme A-expressing CD3+ T cells was evident in the lesions from all patients. Confocal microscopy revealed coexpression of perforin and granulysin, primarily in CD8+ T cells; however, this expression was lower in the tuberculosis lesions. These findings suggest that symptomatic, chronic tuberculosis disease is associated with insufficient up-regulation of perforin and granulysin coexpression in CD8+ T cells at the local site of infection.

* Corresponding author. Mailing address: Center for Infectious Medicine, F59, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden. Phone: 46-8-58587376. Fax: 46-8-7467637. E-mail: susanna.brighenti{at}ki.se

{triangledown} Published ahead of print on 30 July 2007.

Editor: A. D. O'Brien

Infection and Immunity, November 2007, p. 5210-5222, Vol. 75, No. 11
0019-9567/07/$08.00+0     doi:10.1128/IAI.00624-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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