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

Sajjan Mittal, Neil A. Marshall, Linda Duncan, Dominic J. Culligan, Robert N. Barker, Mark A. Vickers

Research output: Contribution to journalArticle

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Abstract

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(+)CD127(low)CD4(+) 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 (R-s = 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%, In = 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.

Original languageEnglish
Pages (from-to)5359-5370
Number of pages12
JournalBlood
Volume111
Issue number11
Early online date27 Feb 2008
DOIs
Publication statusPublished - 1 Jun 2008

Keywords

  • delayed cutaneous hypersensitivity
  • follicular lymphoma
  • peripheral-blood
  • suppressive function
  • myeloid-leukemia
  • FOXP3 expression
  • high numbers
  • lung-cancer
  • in-vitro
  • tumor

Cite this

Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma. / Mittal, Sajjan; Marshall, Neil A.; Duncan, Linda; Culligan, Dominic J.; Barker, Robert N.; Vickers, Mark A.

In: Blood, Vol. 111, No. 11, 01.06.2008, p. 5359-5370.

Research output: Contribution to journalArticle

Mittal, S, Marshall, NA, Duncan, L, Culligan, DJ, Barker, RN & Vickers, MA 2008, 'Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma', Blood, vol. 111, no. 11, pp. 5359-5370. https://doi.org/10.1182/blood-2007-08-105395
Mittal, Sajjan ; Marshall, Neil A. ; Duncan, Linda ; Culligan, Dominic J. ; Barker, Robert N. ; Vickers, Mark A. / Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma. In: Blood. 2008 ; Vol. 111, No. 11. pp. 5359-5370.
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AU - Marshall, Neil A.

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AU - Barker, Robert N.

AU - Vickers, Mark A.

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AB - 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(+)CD127(low)CD4(+) 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 (R-s = 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%, In = 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.

KW - delayed cutaneous hypersensitivity

KW - follicular lymphoma

KW - peripheral-blood

KW - suppressive function

KW - myeloid-leukemia

KW - FOXP3 expression

KW - high numbers

KW - lung-cancer

KW - in-vitro

KW - tumor

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