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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5359-5370.
Prepublished online as a Blood First Edition Paper on February 27, 2008; DOI 10.1182/blood-2007-08-105395.
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Submitted August 6, 2007
Accepted February 19, 2008
Local and systemic induction of CD4+CD25+ regulatory T cell population by non-Hodgkin's lymphoma
Sajjan Mittal, Neil A Marshall, Linda Duncan, D J Culligan, R N Barker, and Mark A. Vickers*
Department of Clinical Haematology, Aberdeen Royal Infirmary, Aberdeen, United Kingdom
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom
* Corresponding author; email: m.a.vickers{at}abdn.ac.uk.
Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin's lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMC) and involved tissues from 30 patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMC (median=20.4% CD4 T cells, n=20) versus healthy controls (median=3.2%, n=13, p <0. 001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (Rs=0.79, p<0.0001). T cell hyporesponsiveness was reversed by depleting CD25+ cells, or by adding anti-CTLA-4, supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median=38.8% CD4 T cells, n=15) versus reactive nodes (median=11.6%, n=2, p=0.02). When autologous CD25- PBMC fractions were incubated with tumor cells from patients (n=6) in vitro, there was consistent strong induction and then expansion of cells with the CD4+CD25+FoxP3+ phenotype of
classic 'natural' Treg cells. This population was confirmed to be suppressive in function. Direct cell-cell interaction of tumor cells with CD25- PBMC was important in Treg induction, although there was heterogeneity in the mechanisms responsible. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.
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