A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis.
Active tuberculosis (TB) is associated with prolonged suppression of Mycobacterium tuberculosis (MTB)-specific immune responses, but mechanisms involved are understood incompletely. We investigated a potential role for CD4+CD25+ regulatory T cells in depressed anti-MTB immunity by evaluating serially CD4 cell phenotype and interferon (IFN)-gamma production by mononuclear cells from patients with TB. At diagnosis, frequencies of CD4+CD25+ T cells were increased in blood from TB patients compared to healthy purified protein derivative (PPD)-positive controls (with a history of prior TB exposure), and remained elevated at completion of therapy (6 months). By contrast, expression of another activation marker, CD69, by CD4 T cells was increased at diagnosis, but declined rapidly to control levels with treatment. Among CD4+CD25+ T cells from TB patients at diagnosis those expressing high levels of CD25, probably representing regulatory T cells, were increased 2.9-fold when compared to control subjects, while MTB-stimulated IFN-gamma levels in whole blood supernatants were depressed. A role for CD4+CD25+ T cells in depressed IFN-gamma production during TB was substantiated in depletion experiments, where CD25+-depleted CD4 T cells produced increased amounts of IFN-gamma upon MTB stimulation compared to unseparated T cells. At follow-up, IFN-gamma production improved most significantly in blood from TB patients with high baseline frequencies of CD4+CD25+ T cells (more than threefold higher than controls for both total and CD25hi+ CD4 T cells), who also had a significant drop in frequencies of both total and 'regulatory' CD4+CD25+ T cells in response to treatment. Expansion of CD4+CD25+ regulatory T cells during active TB may play a role in depressed T cell IFN-gamma production.
Universidade Federal do Espírito Santo, Núcleo Doenças Infecciosas, Vitória, ES, Brazil.
R
R
Ribeiro-Rodrigues
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T
Resende Co
R
R
Rojas
Z
Z
Toossi
R
R
Dietze
W H
WH
Boom
E
E
Maciel
C S
CS
Hirsch
D000328:Adult; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D037181:Lectins, C-Type; D008168:Lung / Q000276:immunology; D008297:Male; D009000:Monocytes / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010641:Phenotype; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D014373:Tuberculin / Q000276:immunology; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D000099192:CD69 Antigens
D000942:Antigens, Bacterial; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D007371:Interferon-gamma; D016753:Interleukin-10; D037181:Lectins, C-Type; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D014373:Tuberculin; D014409:Tumor Necrosis Factor-alpha; D000099192:CD69 Antigens