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Immature NK Cells Suppress Dendritic Cell Functions during the Development of Leukemia in a Mouse Model

Kazumi Ebata^*, Yukihiro Shimizu^1,*, Yasuhiro Nakayama^*, Masami Minemura^*, Jun Murakami^*, Tsutomu Kato^*, Satoshi Yasumura^*, Terumi Takahara^*, Toshiro Sugiyama^* and Shigeru Saito

^* The Third Department of Internal Medicine, Faculty of Medicine, and Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama, Japan

To analyze the mechanisms by which cancer cells escape from hosts’ immune surveillance, we investigated the changes in immune status during the progression of leukemia induced by injecting mice with WEHI-3B cells. In the bone marrow (BM) of leukemic mice, only DX5⁺CD3^– cells were continuously increased, despite the progression of leukemia. In addition, DX5⁺CD3^– cells were rapidly increased in peripheral blood (PB) 20 days after inoculation. We also found that myeloid dendritic cells (DCs) expressing low levels of I-A^d and having low allo-T cell stimulatory activity were markedly increased in PB and spleen. The increase in DX5⁺ cells in BM was thought to be induced by soluble factors from leukemic cells. DX5⁺ cells from leukemic mice were CD3^–, B220^–, Gr-1^–, CD14^–, CD94^–, Ly-49C/F^–, asialo GM1⁺, CD25⁺, CD122⁺, Thy-1^bright, and c-kit^dim and showed low killing activity against YAC-1 cells, suggesting that those DX5⁺ cells were immature NK cells. NK cells from leukemic PB down-regulated the expression of I-A^d on DCs, an effect mediated by TGF-. Moreover, these NK cells significantly suppressed the allo-T cell stimulatory activity of DCs, an effect requiring cell-to-cell contact between NK cells and DCs and thought to involve CD25. Importantly, NK cells from leukemic PB inhibited generation of autotumor-specific CTL induced by DCs in primary MLR or by DC immunization. In conclusion, we identified circulating immature NK cells with immunosuppressive activities. These cells may be important for understanding the involvement of the host immune system during the development of leukemia.