Abstract
We characterized leukemic cells from 20 adult T-cell leukemia (ATL) cases and 7 ATL-derived cell lines in terms of Foxp3 messenger RNA (mRNA) expression, cytokine production, cell surface markers associated with regulatory T-cells (Treg), and in vitro immunoregulatory activity and compared the results with those of cells from 3 T-cell-type chronic lymphocytic leukemia (T-CLL) patients and normal CD4+ T-cells. Real-time polymerase chain reaction analysis showed that cells from 10 ATL cases, 1 T-CLL case, and 1 ATL cell line had higher Foxp3 mRNA levels than CD4+ T-cells. In 5 ATL cases, Foxp3 levels were comparable to those of CD4+CD25+ T-cells. Flow cytometric analysis revealed that CTLA-4 expression correlated with Foxp3 mRNA level in ATL cells. The cells of all ATL cases examined produced no interleukin 2 or interferon γ after ionomycin and phorbolmyristate acetate stimulation. Cases with low Foxp3 expression (Foxp3-low) tended to express higher levels of transforming growth factor β mRNA, but this trend was not statistically significant. An in vitro inhibition assay showed that the proliferation of normal CD4+CD25- T-cells stimulated with anti-CD3 monoclonal antibody and autologous dendritic cells was significantly suppressed by coculture with Foxp3-high ATL cells. These results indicate that Foxp3 expression is variable in ATL cases and that Foxp3-high ATL cells, which resemble Treg phenotypically as well as functionally, may be involved in immune suppression in ATL.
Similar content being viewed by others
References
Uchiyama T, Yodoi J, Sagawa K, Takatsuki K, Uchino H. Adult T-cell leukemia: clinical and hematologic features of 16 cases. Blood. 1977;50:481–492.
Uchiyama T, Hori T, Tsudo M, et al. Interleukin-2 receptor (Tac antigen) expressed on adult T cell leukemia cells. J Clin Invest. 1985;76:446–453.
Yasunaga J, Sakai T, Nosaka K, et al. Impaired production of naive T lymphocytes in human T-cell leukemia virus type I-infected individuals: its implications in the immunodeficient state. Blood. 2001;97:3177–3183.
Uchiyama T, Sagawa K, Takatsuki K, Uchino H. Effect of adult T-cell leukemia cells on pokeweed mitogen-induced normal B-cell differentiation. Clin Immunol Immunopathol. 1978;10:24–34.
Sakaguchi S. Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–562.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–1061.
Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–336.
Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4:337–342.
Katoh T, Harada T, Morikawa S, Wakutani T. IL-2- and IL-2-R-independent proliferation of T-cell lines from adult T-cell leukemia/lymphoma patients. Int J Cancer. 1986;38:265–274.
Maeda M, Shimizu A, Ikuta K, et al. Origin of human T-lym-photrophic virus I-positive T cell lines in adult T cell leukemia: analysis of T cell receptor gene rearrangement. J Exp Med. 1985;162:2169–2174.
Chen H, Hori T, Maeda M, Uchiyama T. Identification of an adhesion molecule expressed on adult T cell leukemia cells derived from a patient with gastrointestinal involvement: implication for a possible role of integrin β7 in leukemic cell infiltration into intestinal mucosa. J Clin Immunol. 1999;19:186–193.
Miyoshi I, Miyamoto K, Sumida M, et al. Chromosome 14q+ in adult T-cell leukemia. Cancer Genet Cytogenet. 1981;3:251–259.
Hori T, Sakaida H, Sato A, et al. Detection and delineation of CXCR-4 (fusin) as an entry and fusion cofactor for T-tropic [correction of T cell-tropic] HIV-1 by three different monoclonal antibodies. J Immunol. 1998;160:180–188.
Morita R, Ukyo N, Furuya M, Uchiyama T, Hori T. Atrial natriuretic peptide polarizes human dendritic cells toward a Th2-promoting phenotype through its receptor guanylyl cyclase-cou-pled receptor A. J Immunol. 2003;170:5869–5875.
Kohno T, Yamada Y, Akamatsu N, et al. Possible origin of adult T-cell leukemia/lymphoma cells from human T lymphotropic virus type-1-infected regulatory T cells. Cancer Sci. 2005;96:527–533.
Ukyo N, Hori T, Yanagita S, Ishikawa T, Uchiyama T. Costimulation through OX40 is crucial for induction of an alloreactive human T-cell response. Immunology. 2003;109:226–231.
Read S, Malmstrom V, Powrie F Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.
Takahashi T, Tagami T, Yamazaki S, et al. Immunologic self-tolerance maintained by CD25+CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med. 2000;192:303–310.
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol. 2002;3:135–142.
Tendler CL, Burton JD, Jaffe J, et al. Abnormal cytokine expression in Sezary and adult T-cell leukemia cells correlates with the functional diversity between these T-cell malignancies. Cancer Res. 1994;54:4430–4435.
Arima N, Daitoku Y, Yamamoto Y, et al. Heterogeneity in response to interleukin 2 and interleukin 2-producing ability of adult T cell leukemic cells. J Immunol. 1987;138:3069–3074.
Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–1886.
Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med. 2001;194:629–644.
Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA. A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol. 2001;166:7282–7289.
Piccirillo CA, Letterio JJ, Thornton AM, et al. CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J Exp Med. 2002;196:237–246.
Klein L, Khazaie K, von Boehmer H. In vivo dynamics of antigenspecific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci U S A. 2003;100:8886–8891.
Diamond MP, El-Hammady E, Wang R, Saed G. Regulation of transforming growth factor-beta, type III collagen, and fibronectin by dichloroacetic acid in human fibroblasts from normal peritoneum and adhesions. Fertil Steril. 2003;79:1161–1167.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Matsubara, Y., Hori, T., Morita, R. et al. Delineation of immunoregulatory properties of adult T-cell leukemia cells. Int J Hematol 84, 63–69 (2006). https://doi.org/10.1532/IJG97.06002
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1532/IJG97.06002