Bacterial DNA and synthetic single-stranded oligonucleotides having unmethylated CpG motifs (CpG-ODN) powerfully stimulate cellular immune responses by an unknown mechanism. There is evidence that internalization of the nucleotide is required for activity. Both CpG-ODN and engagement of CD40 protects WEHI-231 murine B lymphoma cells from apoptosis induced by antibody to surface IgM, and both agents induce interleukin-6 (IL-6) production by these cells. We now report the isolation of CpG-ODN-resistant subclones (designated CR) from WEHI 231 cells, as well as subclones that are sensitive to CpG-ODN (designated CS). CR clones completely fail to respond to CpG-ODN but they retain the capacity to respond normally to engagement of CD40. CR cells incorporate CpG-ODN into small, acidified perinuclear vesicles in the same way as do the parent WEHI 231 cells. The CR, CS, and WEHI 231 cells all had identical cytogenetics. The described CR clones have a stable and specific defect in the mechanism responsible for the intracellular recognition and response to CpG-ODN, suggesting that they harbor a mutation that disables the CpG-ODN detection mechanism. These clones may be useful to determine at a molecular level which proteins and cell components are required for immune cells to detect and respond to CpG-ODN.
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