Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma

Neil Andrew Marshall, L. E. Christie, Laura R Munro, D. J. Culligan, Peter W. Johnston, Robert Norman Barker, Mark Adrian Vickers

Research output: Contribution to journalArticle

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Abstract

Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4(+) T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)-secreting T-regulatory 1 (Tr1) and CD4(+)CD25(+) regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells. (C) 2004 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)1755-1762
Number of pages7
JournalBlood
Volume103
Issue number5
DOIs
Publication statusPublished - Mar 2004

Keywords

  • REED-STERNBERG CELLS
  • VERSUS-HOST DISEASE
  • INTERLEUKIN-13 RECEPTOR
  • IMMUNE-RESPONSES
  • PERIPHERAL-BLOOD
  • TUMOR-CELLS
  • EXPRESSION
  • EBV
  • CYTOKINES
  • CYCLOPHOSPHAMIDE

Cite this

Marshall, N. A., Christie, L. E., Munro, L. R., Culligan, D. J., Johnston, P. W., Barker, R. N., & Vickers, M. A. (2004). Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood, 103(5), 1755-1762. https://doi.org/10.1182/blood-2003-07-2594

Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. / Marshall, Neil Andrew; Christie, L. E.; Munro, Laura R; Culligan, D. J.; Johnston, Peter W.; Barker, Robert Norman; Vickers, Mark Adrian.

In: Blood, Vol. 103, No. 5, 03.2004, p. 1755-1762.

Research output: Contribution to journalArticle

Marshall, NA, Christie, LE, Munro, LR, Culligan, DJ, Johnston, PW, Barker, RN & Vickers, MA 2004, 'Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma', Blood, vol. 103, no. 5, pp. 1755-1762. https://doi.org/10.1182/blood-2003-07-2594
Marshall NA, Christie LE, Munro LR, Culligan DJ, Johnston PW, Barker RN et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood. 2004 Mar;103(5):1755-1762. https://doi.org/10.1182/blood-2003-07-2594
Marshall, Neil Andrew ; Christie, L. E. ; Munro, Laura R ; Culligan, D. J. ; Johnston, Peter W. ; Barker, Robert Norman ; Vickers, Mark Adrian. / Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. In: Blood. 2004 ; Vol. 103, No. 5. pp. 1755-1762.
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abstract = "Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4(+) T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)-secreting T-regulatory 1 (Tr1) and CD4(+)CD25(+) regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells. (C) 2004 by The American Society of Hematology.",
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AU - Marshall, Neil Andrew

AU - Christie, L. E.

AU - Munro, Laura R

AU - Culligan, D. J.

AU - Johnston, Peter W.

AU - Barker, Robert Norman

AU - Vickers, Mark Adrian

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AB - Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4(+) T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)-secreting T-regulatory 1 (Tr1) and CD4(+)CD25(+) regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells. (C) 2004 by The American Society of Hematology.

KW - REED-STERNBERG CELLS

KW - VERSUS-HOST DISEASE

KW - INTERLEUKIN-13 RECEPTOR

KW - IMMUNE-RESPONSES

KW - PERIPHERAL-BLOOD

KW - TUMOR-CELLS

KW - EXPRESSION

KW - EBV

KW - CYTOKINES

KW - CYCLOPHOSPHAMIDE

U2 - 10.1182/blood-2003-07-2594

DO - 10.1182/blood-2003-07-2594

M3 - Article

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SP - 1755

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JO - Blood

JF - Blood

SN - 0006-4971

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ER -