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Published ahead of print on December 9, 2005, doi:10.1164/rccm.200508-1294OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 7, April 2006, 803-810

A more recent version of this article appeared on April 1, 2006
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Submitted on August 20, 2005
Accepted on December 7, 2005

Regulatory T Cells are Expanded in Blood and Disease Sites in Tuberculosis Patients

Valerie Guyot-Revol1, John A Innes2, Sarah Hackforth2, Tim Hinks1, and Ajit Lalvani1*

1 Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom, 2 Department of Infection and Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, United Kingdom

* To whom correspondence should be addressed. E-mail: ajit.lalvani{at}ndm.ox.ac.uk.

Rationale: T cell responses during tuberculosis help contain M. tuberculosis in vivo but also cause collateral damage to host tissues. Immune regulatory mechanisms may limit this immunopathology and suppressed cellular immune responses in tuberculosis patients 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 tuberculosis. Objective: To determine whether regulatory T cells are increased in tuberculosis patients and whether they suppress cellular immune responses. Methods: We compared the frequency of circulating regulatory T cells in 27 untreated tuberculosis patients and 23 healthy controls using two specific markers: cell surface CD25 expression and FoxP3 mRNA expression in peripheral blood mononuclear cells. Measurements and Main Results: We detected a 3-fold 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 tuberculosis patients and there was a positive correlation between these markers (r=0.58, P<0.001). Increased expression of IL-10 and TGF-{beta}1 mRNA was also detected in tuberculosis patients 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 7 of 8 tuberculosis patients (P=0.005). Finally, FoxP3 expression was increased 2.3-fold in extrapulmonary TB patients compared 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 tuberculosis patients and may contribute to suppression of Th1-type immune responses.
Key words: Mycobacterium tuberculosis, CD4+CD25+ regulatory T cells, FoxP3, immunopathology




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