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

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.