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Published online before print June 1, 2007

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(Journal of Leukocyte Biology. 2007;82:576-584.)
© 2007 by Society for Leukocyte Biology

Hodgkin’s Reed-Sternberg cell line (KM-H2) promotes a bidirectional differentiation of CD4⁺CD25⁺Foxp3⁺ T cells and CD4⁺ cytotoxic T lymphocytes from CD4⁺ naive T cells

The First Department of Internal Medicine, Kansai Medical University, Osaka, Japan

¹ Correspondence: The First Department of Internal Medicine, Kansai Medical University, 10-15, Fumizono-Cho, Moriguchi-City, Osaka, 570-8507, Japan. E-mail: shimizto{at}takii.kmu.ac.jp

A recent report revealed that a large population of Hodgkin’s lymphoma-infiltrating lymphocytes (HLILs) consisted of regulatory T cells. In this study, we cocultured CD4⁺ naive T cells with KM-H2, which was established as a Hodgkin’s Reed-Sternberg cell line, to clarify their ability to induce CD25⁺Forkhead box P3⁺ (Foxp3⁺) T cells. The characteristic analyses of T cells cocultured with KM-H2 revealed the presence of CD4⁺CD25⁺ T cells. They expressed CTLA-4, glucocorticoid-induced TNFR family-related gene, and Foxp3 and could produce large amounts of IL-10. Conversely, KM-H2 also generated CD4⁺ CTLs, which expressed Granzyme B and T cell intracellular antigen-1 in addition to Foxp3⁺ T cells. They exhibit a strong cytotoxic effect against the parental KM-H2. In conclusion, KM-H2 promotes a bidirectional differentiation of CD4⁺ naive T cells toward Foxp3⁺ T cells and CD4⁺ CTLs. In addition to KM-H2, several cell lines that exhibit the APC function were able to generate Foxp3⁺ T cells and CD4⁺ CTLs. Conversely, the APC nonfunctioning cell lines examined did not induce both types of cells. Our findings suggest that the APC function of tumor cells is essential for the differentiation of CD4⁺ naive T cells into CD25⁺Foxp3⁺ T cells and CD4⁺ CTLs and at least partly explains the predominance of CD25⁺Foxp3⁺ T cells in HLILs and their contribution to a better prognosis. Therefore, in APC-functioning tumors, including classical Hodgkin lymphomas, which generate Foxp3⁺ T cells and CD4⁺ CTLs, these T cell repertories play a beneficial role synergistically in disease stability.

Key Words: antigen-presenting cell • tumor surveillance • regulatory T cell • neoplastic cell