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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 356, (2006)
© 2006 American Thoracic Society

Correspondence

FoxP3 mRNA Expression in Regulatory T Cells from Patients with Tuberculosis

To the Editor:

We read with great interest the article by Guyot-Revol and colleagues (1) assessing the role of T regulatory cells (Tregs) in tuberculosis (TB) pathogenesis. Guyot-Revol and coworkers found that in patients with TB, percentages of CD4+CD25high T cells and levels of FoxP3 mRNA expression in peripheral blood mononuclear cells were both significantly higher in comparison with controls. To better comprehend Tregs' mechanism of action, the authors investigated whether the increased levels of FoxP3 mRNA that they had observed were effectively caused by increased gene expression, or were simply the result of increased CD4+CD25high frequency. FoxP3 mRNA in CD4+CD25+ T cells was compared between patients with TB and control subjects. As no quantitative difference was observed, the authors suggest that the greater levels of FoxP3 mRNA are simply an effect of increases in Treg frequency rather than a result of an up-regulated gene expression.

The transcription factor FoxP3 is the most specific molecular marker for Tregs available to date, and its correct evaluation is crucial (2–4). In the analysis of Treg dynamics, an assessment of what happens in the frequency and level of FoxP3 mRNA expression at the single cell level is mandatory. The recent literature demonstrates a strong correlation between levels of CD25 expression and the frequency of FoxP3-positive cells in healthy donors (4), and suggests that to correctly evaluate FoxP3 expression in Tregs, mRNA should be quantified in CD4+CD25high, rather than in CD4+CD25+ T cells (5).

We are currently performing a prospective study to evaluate Tregs in patients with TB. Analysis of CD4+CD25high percentage on CD4 T cells at TB diagnosis showed similar levels of Tregs among patients with TB and controls (median percentage: 2.1% [IQR, 1.8–6.6] vs. 1.9% [IQR, 1.5–2.2]). Unlike Guyot-Revol and coworkers, we evaluated FoxP3 mRNA expression by real-time polymerase chain reaction in CD4+CD25high T cells, purified using an EPICS ALTRA Cell Sorter (Beckman-Coulter; purity > 93.6%). A considerable increase of FoxP3 mRNA expression in patients with TB with respect to control subjects was clearly observed (median: 39.1 [IQR, 5.1–109] vs. 1.6 [IQR, 0.8–2.8]; p < 0.0062). These data implicate FoxP3 gene overexpression as a probable mechanism involving Tregs in the pathogenesis of TB, and suggest a possible role of FoxP3 gene up-regulation in the outcome of chronic infections.

Our results underscore the importance of using the correct methodology in evaluating Treg cell dynamics, and prove that an accurate evaluation of FoxP3 mRNA expression in Treg cells may lead to the identification of previously unknown mechanisms of Treg cell involvement in disease pathogenesis.

Lidia Gazzola, Camilla Tincati and Andrea Gori

"San Paolo" Hospital, University of Milan, Milan, Italy

Marina Saresella and Ivana Marventano

"Don C. Gnocchi" Foundation, IRCCS, Milan, Italy

Fabio Zanini

"Luigi Sacco" Hospital, University of Milan, Milan, Italy

FOOTNOTES

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

REFERENCES

  1. Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A. Regulatory T cells are expanded in blood and disease sites in tuberculosis patients. Am J Respir Crit Care Med 2006;173:803–810.[Abstract/Free Full Text]
  2. Viguier M, Lemaitre F, Verola O, Cho M-S, Gorochov G, Dubertret L, Bachelez H, Kourilsky P, Ferradini L. FoxP3 expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol 2004;173:1444–1453.[Abstract/Free Full Text]
  3. Fontenot JD, Gavin MA, Rudensky AY. FoxP3 programs the development and function of CD4+CD25+regulatory T cells. Nat Immunol 2003;4:330–336.[CrossRef][Medline]
  4. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cells development and the forkhead family transcription factor FoxP3. Nat Immunol 2005;6:331–337.[CrossRef][Medline]
  5. Rocandor G, Brown PJ, Maestre L, Hue S, Martinez-Torrecuadrada JL, Ling K-L, Pratap S, Toms C, Fox BC, Cerundolo V, et al. Analysis of FoxP3 protein expression in human CD4+CD25+ regulatory T cells at the single-cell level. Eur J Immunol 2005;35:1681–1691.[CrossRef][Medline]



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Copyright © 2006 American Thoracic Society