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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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NEOPLASIA

Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma

Sajjan Mittal1, Neil A. Marshall2, Linda Duncan2, Dominic J. Culligan1, Robert N. Barker2, and Mark A. Vickers2

1 Department of Clinical Haematology, Aberdeen Royal Infirmary, Aberdeen; and 2 Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom

Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMCs) and involved tissues from 30 patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMCs (median = 20.4% CD4 T cells, n = 20) versus healthy controls (median = 3.2%, n = 13, P < .001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (Rs = 0.79, P < .001). 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 = .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– PBMCs 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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