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Originally published online as doi:10.2353/ajpath.2009.080941 on May 12, 2009

Published online before print May 12, 2009
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(American Journal of Pathology. 2009;174:2211-2224.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080941

Compartmentalization of Immune Responses in Human Tuberculosis

Few CD8+ Effector T Cells but Elevated Levels of FoxP3+ Regulatory T Cells in the Granulomatous Lesions

Sayma Rahman*, Berhanu Gudetta{dagger}, Joshua Fink*, Anna Granath{ddagger}, Senait Ashenafi*§, Abraham Aseffa, Milliard Derbew||, Mattias Svensson*, Jan Andersson*** and Susanna Grundström Brighenti*

From the Center for Infectious Medicine,* and the Division of Infectious Diseases,** Department of Medicine, the Ear, Nose and Throat Clinic,{ddagger} Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden; the Departments of Paediatrics,{dagger} Pathology,§ and Surgery,|| Faculty of Medicine, Addis Ababa University and Tikur Anbessa Hospital, Addis Ababa, Ethiopia; and the Armauer Hansen Research Institute, Addis Ababa, Ethiopa

Immune responses were assessed at the single-cell level in lymph nodes from children with tuberculous lymphadenitis. Tuberculosis infection was associated with tissue remodeling of lymph nodes as well as altered cellular composition. Granulomas were significantly enriched with CD68+ macrophages expressing the M. tuberculosis complex-specific protein antigen MPT64 and inducible nitric oxide synthase. There was a significant increase in CD8+ cytolytic T cells surrounding the granuloma; however, CD8+ T cells expressed low levels of the cytolytic and antimicrobial effector molecules perforin and granulysin in the granulomatous lesions. Quantitative real-time mRNA analysis revealed that interferon-{gamma}, tumor necrosis factor-{alpha}, and interleukin-17 were not up-regulated in infected lymph nodes, but there was a significant induction of both transforming growth factor-β and interleukin-13. In addition, granulomas contained an increased number of CD4+FoxP3+ T cells co-expressing the immunoregulatory cytotoxic T-lymphocyte antigen-4 and glucocorticoid-induced tumor necrosis factor receptor molecules. Low numbers of CD8+ T cells in the lesions correlated with high levels of transforming growth factor-β and FoxP3+ regulatory T cells, suggesting active immunosuppression at the local infection site. Compartmentalization and skewing of the immune response toward a regulatory phenotype may result in an uncoordinated effector T-cell response that reduces granule-mediated killing of M. tuberculosis-infected cells and subsequent disease control.


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