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Dynamics of Generation of Antigen Loss Variants from L1210 Murine Leukemia Clones Detected by a Tumor-specific T-Cell Clone¹

Department of Medical Technology [F. N.], Nagoya University College of Medical Technology, 1-1-20 Daikominami, Higashi-ku, Nagoya, Aichi 461; Department of Immunology [S. M. J. R., K. I., T. Y., I. N.], The First Department of Internal Medicine [K. K., E. N.] and Clinical Laboratory [K. K.], Nagoya University School of Medicine, Nagoya 466; and Department of Microbiology [T. Y.], Fukui Medical College, Fukui 910-11, Japan

Originally T-cell clone K7L-sensitive L1210 murine leukemia clones were tested for their capacity to generate K7L-insensitive variants at various times after cloning. All of the L1210 clones (L1210/1, -2, -4, and -7) maintained in vitro for 1 month were severely inhibited in their growth in the culture in which K7L was added and in mice given injections of K7L at the initial stage. This indicated that any L1210 clone tested was not a mixture of K7L-sensitive and K7L-insensitive clones at the time of cloning. By both in vivo and in vitro K7L-mediated tumor suppression assays, K7L-insensitive antigen loss variants were then found to be generated from some (L1210/4, L1210/7) but not other (L1210/1, L1210/2) originally K7L-sensitive L1210 clones during 1 month of maintenance. Ratios of variant cells to total clone cells 1 month after cloning were estimated around 0.1% for L1210/7, 0.01% for L1210/4, and <0.001% (undetectable) for L1210/1 and L1210/2. Neither L1210/1 nor L1210/2 generated detectable K7L-insensitive variant cells during long-term (14-month) maintenance. All of the ten subclones of L1210/7 which were obtained 7 or 11 months after the initial cloning of L1210/7 were K7L sensitive, and not all the subclones generated K7L-insensitive variants in 1–2 months of maintenance after recloning. However, all of the subclones of L1210/7 which were maintained for 7 months generated antigen loss variants. All eight clone cells obtained from original L1210 and K7L-insensitive L1210 expressed H-2K^d and H-2D^d antigens detected by H-2K^d or D^d-specific cytotoxic T-lymphocyte clones or monoclonal antibodies. These results suggest that the antigen loss variants arise in originally K7L-sensitive L1210 clones at different times after cloning, and the probability of generation of the variants is clonally determined. The antigen loss variants seem to be generated by rare (once per 1 to 2 months or less frequent) chance with unproportionally rapid growth rather than by more frequent development for simple accumulation. The ratio of K7L-insensitive variant cells to total L1210/7 cells did not increase progressively during long-term (13 months or more) maintenance in vivo or in vitro and was always below 0.1%. It was suggested that the population size of antigen loss variants was controlled biphasically.

¹ This research was supported in part by The Ishida Foundation and by Aichi Cancer Center.

² To whom requests for reprints should be addressed.

Received 4/27/87. Revised 8/11/87. Accepted 9/ 3/87.