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Published ahead of print on December 9, 2005, doi:10.1164/rccm.200508-1294OC
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American Journal of Respiratory and Critical Care Medicine Vol 173. pp. 803-810, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200508-1294OC

Original Article

Regulatory T Cells Are Expanded in Blood and Disease Sites in Patients with Tuberculosis

Valerie Guyot-Revol, John A. Innes, Sarah Hackforth, Tim Hinks and Ajit Lalvani

Tuberculosis Immunology Group, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, United Kingdom

Correspondence and requests for reprints should be addressed to A. Lalvani, D.M., Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Level 7, Oxford OX3 9DU, UK. E-mail: ajit.lalvani{at}ndm.ox.ac.uk

Rationale: T-cell responses during tuberculosis (TB) help contain Mycobacterium tuberculosis in vivo but also cause collateral damage to host tissues. Immune regulatory mechanisms may limit this immunopathology, and suppressed cellular immune responses in patients with TB suggest the presence of regulatory activity. CD4+CD25high regulatory T cells mediate suppressed cellular immunity in several chronic infections but have not been described in TB.

Objective: To determine whether regulatory T cells are increased in patients with TB and whether they suppress cellular immune responses.

Methods: We compared the frequency of circulating regulatory T cells in 27 untreated patients with TB and 23 healthy control subjects using two specific markers: cell-surface CD25 expression and FoxP3 mRNA expression in peripheral blood mononuclear cells.

Measurements and Main Results: We detected a threefold increase in the frequency of CD4+CD25high T cells (p < 0.001) and a 2.2-fold increase in FoxP3 expression (p = 0.006) in patients with TB, and there was a positive correlation between these markers (r = 0.58, p < 0.001). Increased expression of interleukin-10 and transforming growth factor-beta1 mRNA was also detected in patients with TB but did not correlate with regulatory T-cell markers. Ex vivo depletion of CD4+CD25high cells from peripheral blood mononuclear cells resulted in increased numbers of M. tuberculosis antigen–specific IFN-{gamma}–producing T cells in seven of eight patients with TB (p = 0.005). Finally, FoxP3 expression was increased 2.3-fold in patients with extrapulmonary TB compared with patients with purely pulmonary TB (p = 0.01) and was amplified 2.6-fold at disease sites relative to blood (p = 0.043).

Conclusions: Regulatory T cells are expanded in patients with TB and may contribute to suppression of Th1-type immune responses.

Key Words: CD4+ • CD25+ • regulatory T cells • FoxP3 • immunopathology • Mycobacterium tuberculosis




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