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

Abstract

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+CD25(high) regulatory T cells mediate suppressed cellular immunity in several chronic infections but have not been described in TB. To determine whether regulatory T cells are increased in patients with TB and whether they suppress cellular immune responses. 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. We detected a threefold increase in the frequency of CD4 + CD25(high) 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 + CD25(high) 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). Regulatory T cells are expanded in patients with TB and may contribute to suppression of Th1-type immune responses.